Erythropoeitin production by electrical stimulation

ABSTRACT

Described herein are methods, devices, and systems for treating human anemia. The methods, devices, and systems generally include monitoring a patients hemoglobin level and at least one of autonomic balance and inflammatory state to determine the etiology of the anemic state, modulating at least one of a sympathetic or parasympathetic nerve based on the cause of the anemia, monitoring for changes in the patients cardiac activity and state of inflammation, and hemoglobin level. An external neurostimulation system is describes, and well as a chronic implantable system. A method for treating a patient for anemia in conjunction with a renal denervation ablation catheter is also disclosed.

PRIORITY CLAIM

This application claims the benefit of U.S. Provisional Application No.61/801,459, filed Mar. 15, 2013 and is incorporated herein by referencein its entirety to provide continuity of disclosure.

TECHNICAL FIELD

This application relates generally to implantable stimulation devicesand, more specifically, but not exclusively to providing electricalstimulation to increase the production of erythropoietin.

BACKGROUND

Anemia is defined by the World Health Organization's as hemoglobinconcentration<13.0 g/dl in men and <12.0 g/dl in women. Approximatelynine percent of the general adult population meets this definition ofanemia. The prevalence of anemia ranges from less than 10% amongpatients with mild heart failure to more than 50% for those withadvanced disease.

Anemia has been shown to be a powerful predictor of rehospitalizationrates and survival in chronic heart failure. Most studies have shown alinear relationship between hematocrit or hemoglobin and survival withthe SOLVD (Studies of Left Ventricular Dysfunction) trial reporting a2.7% increase in the adjusted risk of death per 1% reduction inhematocrit and the PRAISE (Prospective Randomized Amlodipine SurvivalEvaluation) trial describing a 3% increase in risk for each 1% declinein hematocrit. The significance of anemia among patients hospitalizedwith acute decompensated heart failure has been examined. Felker et al.retrospectively analyzed the OPTIME-CHF (Outcomes of a Prospective Trialof Intravenous Milrinone for Exacerbations of Chronic Heart Failure)results and found that hemoglobin level independently predicted adverseevents, even after adjustment for other covariates. For every 1 g/dldecrease in admission hemoglobin value, a 12% increase in theprobability of death or rehospitalization within 60 days of treatmentwas observed. Recently, the same investigators studied anemia inpatients with heart failure and preserved systolic function. Anemia wasonce again found to be independently associated with adverse outcomes(adjusted hazard ratio: 1.6 to 1).

Chemotherapy-induced anemia (CIA) is a frequent complication in cancerpatients receiving conventional myelosuppressive chemotherapy. Anemiaaffects up to 90% of cancer patients. The relative risk of death inpatients with cancer has been determined to increase by 65% in thepresence of anemia. Anemia as an independent prognostic factor forsurvival in patients with cancer: a systematic, quantitative review.Caro J J, Salas M, Ward A, Goss G, Cancer, 2001; 91:2214-2221.

In the case of Hodgkin's lymphoma, a cancer that is currently curable inapproximately two thirds of patients, a hemoglobin level of less than10.5 g/dl at the time of diagnosis is one of seven risk factors. Thehemoglobin level is the strongest of three risk factors at relapse.There is a statistically significant difference in overall survival timebetween females having a hemoglobin level of less than 10.5 g/dl andfemales having a hemoglobin level of greater than 10.5 g/dl. There isalso a statistically significant difference in overall survival timebetween males having a hemoglobin level of less than 12 g/dl and maleshaving a hemoglobin level of greater than 12 g/dl.

The glycoprotein hormone erythropoietin (EPO) is the principal factorresponsible for the regulation of red blood cell production. EPO acts inconcert with other factors to stimulate the proliferation and maturationof responsive bone marrow erythroid precursors. EPO affects expansion ofprogenitor cells by repressing apoptosis (programmed cell death) and byacting as a mitogen to increase production. EPO, along with otherfactors, also decreases the maturation time of red blood cells in thebone marrow.

Erythropoeitic agents have been shown to reduce the need for bloodtransfusions and their associated complications in cancer patientsundergoing chemotherapy, as demonstrated by several clinical trials.Daily subcutaneous administration of EPO stimulation therapyadministration at a dose of 5000 IU increases hemoglobin levels andreduces transfusion requirements in chemotherapy-induced anemia,especially during platinum-based chemotherapy. (Oberhoff et al. (1998)Ann Oncol 9:255-260.) However, it is estimated that 30% to 50% ofpatients undergoing chemotherapy and receiving EPO stimulation therapytreatment are hyporesponsive or refractory to the recombinant EPOtherapy. (J. Glaspy (2005) Expert Opin. Emerging Drugs 10:553-567.) Inaddition, synthetic EPO is known to have serious issues. Bloodtransfusions are also associated with negative consequences, such asiron overload which can cause cancer and/or death due to end-stage organfailure.

EPO is produced primarily in the kidney by endothelium of peritubularcapillaries in the renal cortex. Additionally, the liver, macrophages inthe bone marrow, and astrocytes in the central nervous system (CNS) makesmall amounts of EPO.

Various techniques are described herein for providing electricalstimulation to increase the production and efficacy of erythropoietin.Such techniques are optionally implemented, for example, in patientssuffering from anemia from a variety of etiologies.

SUMMARY

A summary of several sample aspects of the disclosure follows. It shouldbe appreciated that this summary is provided for the convenience of thereader and does not wholly define the breadth of the disclosure. Forconvenience, one or more aspects or embodiments of the disclosure may bereferred to herein simply as “some aspects” or “certain embodiments.”

The disclosure relates in some aspects to electrical stimulation forincreasing erythropoietin production.

The disclosure relates in some aspects to stimulation of the intrinsicnervous system at the heart in order to restore a healthy balance of thesympathetic nervous system in order to treat anemia.

The disclosure relates in some aspects to renal nerve stimulation forincreasing erythropoietin production.

The disclosure relates in some aspects to spinal cord stimulation forincreasing red blood cell production.

The disclosure relates in some aspects to deep brain stimulation forincreasing erythropoietin production. In certain embodiments, thehypothalamus is stimulated to increase erythropoietin production. Incertain embodiments, the medulla oblongata is stimulated to increaseerythropoietin production. In certain embodiments, the hypothalamus inblocked in order to decrease inflammation.

The disclosure relates in some aspects to carotid sinus nerve (CSN)stimulation for increasing erythropoietin production.

The disclosure relates in some aspects to cervical nerve stimulation forincreasing erythropoietin production.

The disclosure relates in some aspects to chemical stimulation of thekidneys to produce EPO.

The disclosure relates in some aspects to stimulation of sympatheticganglion of the parathyroid gland for increasing erythropoietinproduction.

The disclosure relates in some aspects to vagus nerve stimulation forincreasing red blood cell production and inhibition of the production ofinflammatory cytokines.

In certain embodiments, the system may be a closed-loop system thatcontinuously monitors for quality and quantity of blood production foroversight.

In certain embodiments, the system includes multiple sensors that maydetermine EPO, nitrogen oxide, hemoglobin, hematocrit, hepcidin, iron,ferritin, transferrin, serum albumin, Vitamin B12, folate,25-hydroxyvitamin D, phosphate, oxygen, carbon dioxide, creatinine,blood urea nitrogen, compound activation potential of a nerve,anti-inflammatory cytokine concentrations, pro-inflammatory cytokineconcentrations, heat shock protein (HSPs) levels (indicative ofinflammation), blood pressure, pH, and/or impedance, which may be usedto determine the cause of anemia, an appropriate therapeutic strategy,to continuously monitor for quality and quantity of blood production andthe effect of changes on EPO, and to adjust the system's parameters in aclosed-loop.

In certain embodiments, the system adjusts the neuromodulation based onthe monitored cardiac integrity, inflammation markers, EPOconcentration, hemoglobin concentration, blood pressure and/or bloodvolume of the patient.

Adjusting the neuromodulation comprises modifying at least one of aplurality of electric activation parameters including a current level, apulse width, a frequency, a duty cycle, and a location of the patient'sbody to which the electric activation is applied.

Adjusting the electric activation may comprise referring to a lookuptable which provides electric activation plans for different conditionsof monitored sympathetic balance, EPO, inflammation marker, bloodpressure, and blood volume, the electric activation plans eachspecifying a setting of at least one of a plurality of electricactivation parameters including a current level, a pulse width, afrequency, a duty cycle, and a location of the patient's body to whichthe electric activation is applied.

In certain embodiments, the renal nerves are ablated prior toneurostimulation.

The disclosure relates in some aspects to an exterior neurostimulatorthat can be used to treat anemia.

The disclosure relates in some aspects to an implantable neurostimulatorthat can be used to treat anemia.

The disclosure relates in some aspects to determining whether a patientis having an acute episode of heart failure prior to initiatingneurostimulation to treat anemia.

The disclosure relates in some aspects to methods of determininginflammation using a nerve's compound action potential.

The disclosure relates in some aspects to methods of determininginflammation specifically caused by EPO stimulation.

These and other features and advantages of the present invention willbecome apparent to those of ordinary skill in the art in view of thefollowing detailed description of the specific embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features, aspects, and advantages will be more fullyunderstood when considered with respect to the following detaileddescription, the appended claims, and the accompanying drawings,wherein:

FIG. 1 is a simplified diagram of a stimulation device implanted in apatient according to certain embodiments;

FIG. 2 is a functional block diagram of an exemplary stimulation device;

FIGS. 3A and 3B are perspective views of assemblies of ablation and/orneuromodulation elements for a catheter according to certain embodimentsof the present invention;

FIG. 4 is an approximate anatomic diagram that includes the right andleft carotid body and sinus and an exemplary method for providing neuralstimulation;

FIG. 5 is an approximate anatomical diagram of a unit of the carotidbody responsive to chemical changes;

FIG. 6A is a simplified flowchart of an embodiment for determining apatient's inflammatory state according to certain embodiments;

FIG. 6B is a simplified flowchart of an embodiment for determining apatient's inflammatory state according to certain embodiments;

FIG. 7 is a block diagram of an exemplary method for acquisition ofcompound action potentials and analysis of such potentials.

FIG. 8 is a block diagram of an exemplary method for acquisition ofcompound action potentials and analysis of such potentials.

FIG. 9 is a block diagram of an exemplary method for acquisition ofcompound action potentials and analysis of such potentials.

FIG. 10 is a block diagram of an exemplary method for acquisition ofintrinsic compound action potentials and analysis of such potentials.

FIG. 11 is a diagram of an exemplary system that includes an implantabledevice for acquiring compound action potentials and various externaldevices that may analyze such potentials and/or provide for assessmentof inflammation caused by electrical stimulation of a nerve according tocertain embodiments.

FIG. 12 is a simplified flowchart of an embodiment for triggering theinitiation of neurostimulation therapy for treatment of anemia accordingto certain embodiments;

FIG. 13 is a simplified flowchart of an embodiment providing a treatmentmethod according to certain embodiments;

FIG. 14 illustrates an example placement of external stimulation devicesand a system for treating anemia according to certain embodiments;

FIG. 15 illustrates an example method according to certain embodiments;

FIG. 16 illustrates an example method according to certain embodiments.

In accordance with common practice the various features illustrated inthe drawings may not be drawn to scale. Accordingly, the dimensions ofthe various features may be arbitrarily expanded or reduced for clarity.In addition, some of the drawings may be simplified for clarity. Thusthe drawings may not depict all of the components of a given apparatusor method. Finally, like reference numerals may be used to denote likefeatures throughout the specification and figures.

DETAILED DESCRIPTION

The description that follows sets forth one or more illustrativeembodiments. It will be apparent that the teachings herein may beembodied in a wide variety of forms, some of which may appear to bequite different from those of the disclosed embodiments. Consequently,the specific structural and functional details disclosed herein aremerely representative and do not limit the scope of the disclosure. Forexample, based on the teachings herein one skilled in the art shouldappreciate that the various structural and functional details disclosedherein may be incorporated in an embodiment independently of any otherstructural or functional details. Thus an apparatus may be implementedor a method practiced using any number of the structural or functionaldetails set forth in any disclosed embodiment(s). Also, an apparatus maybe implemented or a method practiced using other structural orfunctional details in addition to or other than the structural orfunctional details set forth in any disclosed embodiment(s).

Overview Production of EPO

Erythropoietin (EPO) is produced by peritubular fibroblasts of the renalcortex of the kidney in response to local oxygen tension (renalinterstitial PO₂). PO₂ in the renal cortex is proportional to the ratioof glomerular filtration rate (GFR) (O₂ consumption) to renal blood flow(RBF) (O₂ delivery). The higher the ratio of GFR to RBF (the filtrationfraction), the more O₂ extracted per liter of blood flow in the renalcortex. Reduced oxygen tension in the peritubular fibroblasts of therenal cortex is associated with increased intracellular concentrationsof reactive oxygen species, which, in turn, increases activation ofhypoxia inducible factor-1 (HIF-1) and erythropoietin gene expression.

Under hypoxic conditions, the production of EPO begins within minutes tohours and reaches a maximum production within 24 hours. Hypoxiagenerates a detectable increase in serum EPO within 90 minutes. New redblood cells may not appear until about 5 days later. When largequantities of EPO are formed and there is sufficient iron and requirednutrients (e.g., folic acid, vitamin B12, and vitamin D), the rate ofred blood cell production can increase over ten fold.

The production of EPO is controlled at the transcriptional level. Thehypoxia-inducible transcription factors (HIFs) are inactivated innormoxia by enzymatic hydroxylation of their α-subunits. Hypoxiaattenuates the inhibition of the EPO promoter by GATA-2 and promotes theavailability of heterodimeric (α/β) HIFs (predominantly HIF-2) whichstimulate the EPO enhancer. Levels of the HIF-1α subunit increaseexponentially as O₂ concentration declines. Three HIF-α prolylhydroxylases (PHD-1, -2 and -3) initiate proteasomal degradation ofHIF-α, while an asparaginyl hydroxylase (“factor inhibiting HIF”, FIH-1)inhibits the transactivation potential. The HIF-α hydroxylases containFe2+ and require 2-oxoglutarate and ascorbate as co-factors. HIF israpidly degraded upon reoxygenation. In the presence of oxygen, there isa hydroxylation of a proline residue within a highly conserved region inthe oxygen-dependent degradation domain of HIF-1α. This structuralmodification of HIF-1α enables it to bind to von Hippel-Lindau protein,an interaction necessary for the ubiquitination of HIF-1α and itsdegradation within the proteasome.

EPO binds to EPO receptors (EPOR) on erythroid progenitor cells (burstforming units-erythroid (BFU-E) and colony-forming-unit-erythroid(CFU-E)) in the bone marrow to initiate erythropoiesis. Duringerythropoiesis large amounts of iron are used by the bone marrow tosynthesize hemoglobin. In the liver, HIF-1 stimulates the absorption anddelivery of iron to the bone marrow by repressing the gene encodinghepcidin, an inhibitor of ferroportin, the main protein responsible forintestinal iron uptake. HIF-1 also activates hepatic synthesis oftransferrin, the main plasma protein responsible for transporting ironfrom the intestine to the bone marrow via the transferrin receptor.

In non-neuronal cells, binding of EPO triggers dimerization of EPOreceptors resulting in JAK2 activation. Three different signaltransduction pathways are predominantly activated thereafter: theRAS/RAF/ERK (ERK1/2) pathway; the PI3K/Akt pathway; and the SignalTransducer and Activator of Transcription 5 (STAT5), which uponphosphorilation by JAK2 translocates to the nucleus and initiatestranscription of anti-apoptotic genes, including Bcl-XI.

The Inflammatory Response to Hypoxia

EPO has been shown to have a bell-shaped dose response curve both invitro and in vivo. While too little EPO may be ineffective, EPOoverproduction initiates a pro-inflammatory response by, e.g.,stimulating the production of pro-inflammatory cytokines, which suppressthe effectiveness of the EPO. Sustained hypoxia leads to the activationof nuclear factor κB (NF-κB). NF-κB plays a central role in theinflammatory response with an increased production of pro-inflammatorycytokines including tumour necrosis factor α (TNF-α), interleukin 6(IL-6), interleukin 8 (IL-8), and high mobility group box 1 (HMGB1).

Hypoxia, and specifically HIF-1, is a potent and rapid inducer of theproinflammatory cytokine macrophage migration inhibitory factor (MIF).MIF, in turn, is a key regulator of the hypoxia-induced HIF-1α proteinexpression involving the MIF receptor CD74, thus forming an autocrinepositive-feedback loop. Under hypoxia, MIF is released fromintracellular stores and induces signaling cascades via CD74 to promotehypoxia-induced expression/stabilization of HIF-1α. HIF-1α is importedinto the nucleus and dimerizes with its partner HIF-1β to induce HIF-1target genes, such as MIF itself. This autoamplifying feedback loop isinterrupted by high doses of anti-inflammatory glucocorticoids (GCs) viathe GC receptor (GCR) or the inhibition of HIF-1αexpression/stabilization under normoxia.

MIF acts on macrophages to induce release of many proinflammatorymediators, such as IL-6, and serves as the upstream regulator of TNF-α.MIF's function is unique among cytokines and its effects extend tomultiple processes fundamental to tumorigenesis such as tumorproliferation, evasion of apoptosis, angiogenesis and invasion. Thesepleiotropic functional aspects are paralleled by MIF's unique signalingproperties, which involve activation of the ERK-1/2 and AKT pathways andthe regulation of JAB1, p53, SCF ubiquitin ligases and HIF-1. Theseproperties reflect features central to growth regulation, apoptosis andcell cycle control. The significance of these pro-tumorigenic propertieshas found support in several in vitro and in vivo models of cancer andin the positive association between MIF production and tumoraggressiveness and metastatic potential in a variety of human tumors.

Furthermore, both MIF and TNF-α have been shown to impair erythroidcolony formation, MIF activates HIF-1α under hypoxic conditions, whichserves to activate a pro-angiogenic transcriptional program that isnecessary for tumor progression. MIF downregulates the NK cell receptorNKG2D, thereby impairing NK cell cytoxicity toward tumor cells andupregulating the anti-angiogenic factor thrombospondin-1.

In healthy subjects, the vagus nerve senses inflammation andsignificantly and rapidly inhibits such inflammation by releasing theneurotransmitter acetylcholine. Action potentials transmitted in thevagus nerve activate the efferent arm (the Cholinergic anti-inflammatorypathway) of the Inflammatory Reflex, the neural circuit that convergeson the spleen to inhibit the production of TNF and other cytokines bymacrophages there. Upon excitation, the vagus nerve releasesacetylcholine. The vagus nerve and cholinergic agonists inhibit systemicinflammation by activating the noradrenergic splenic nerve via the α7nicotinic acetylcholine receptor subunit (α7nAChR). α7nAChR is a memberof the family of ligand-gated ion channels. After combining withacetylcholine, this ligand binding receptor transmits cholinergicanti-inflammatory signals into the cytoplasm to activate Janus kinase 2(JAK2). The phosphorylation of JAK2 then triggers phosphorylation ofsignal transducers and activators of transcription 3 (STAT3) andpromotes its dimerization. The phosphorylated STAT3 translocates fromthe cytoplasm into the nucleus. STAT3 then acts as a competitor to NF-κBto bind DNA, which results in a decrease in the production ofpro-inflammatory cytokines, including TNF-α, high mobility group box 1protein (HMGB1), macrophage inflammatory protein-2 (MIP-2), and IL-6.Acetylcholine also augments the production of prostacyclin (PGI₂), apotent vasodilator and anti-inflammatory molecule.

However, under pathological conditions the inflammatory reflex may bedeficient. In such patients, overstimulation of pro-inflammatorycytokines may induce anemia by suppression of erythroid colony formation(MIF/TNF_(α)/IL-1β) on the one hand and impairment of iron utilization(IL-6/hepcidin) on the other. Forms of anemia that are caused byinsufficient numbers of EPO-sensitive erythroid colony-forming unit(CFU-E) cells do not respond well to EPO.

HMGB1 is a late cytokine mediator of the systemic inflammatory response.Increased plasma levels of HMGB1 have been shown to occur 12-24 hoursafter an increase in TNF-α levels, HMGB1 can then induce macrophages,neutrophils, and endothelium to amplify the pro-inflammatory cytokinecascade, MHGB1 can interact with toll-like receptors and the receptorfor advanced glycation end products that further activate innate immuneresponses. These mediators activate infiltrating macrophages andendothelium, further increasing the release of HMGB1 as well as othercytokines, including TNF-α.

The inflammatory response also causes high levels of NO (nitric oxide)to be produced after iNOS (inducible nitric oxide) expression isinduced, mainly in macrophages. NO reacts with concomitantly producedsuperoxide anions, thereby generating highly toxic compounds such asperoxynitrite and hydroxyl radicals.

Interaction Between Erythropoiesis and the Inflammatory Response

EPO and TNF-α have been shown to regulate each other in thehematopoietic system. EPO regulates TNF-α levels and erythropoiesis isinhibited by TNF-α. The circulating concentration of EPO has been shownto initially greatly increase (the plasma level of EPO may rise1000-fold) following an anemic or hypoxaemic stimulus and subsequentlydeclines despite continued hypoxia, likely due to the counteraction ofthis inflammatory response. In vivo administration of LPS and IL-1 hasbeen shown to inhibit hypoxia-induced renal EPO mRNA levels in plasmaEPO in rats, IL-1 has been shown to strongly activate NF-κB, which is alikely suppressor of the EPO promoter. In addition, during inflammation,hepatocyte nuclear factor 4 (HNF-4), a positive transcription factor, islowered and GATA-2, a negative regulating transcription factor, iselevated. TNF-α produced during hypoxia profoundly inhibits apoptosis ofpolymorphonuclear cells (PMNs). Apoptosis of PMNS is a fundamentalmechanism to halt inflammation.

Excessive inflammatory cytokine production acts to interfere with EPOactivity in the bone marrow, reduces iron supply to the bone marrow, andupregulates the production of white blood cells, causing fewer stemcells to differentiate into red blood cells. A decrease in serum albuminconcentration may signal the presence of inflammation.

The Spleen

The spleen is a major source of the initiation of systemic inflammationvia the production of inflammatory cytokines. Electric stimulation ofthe splenic nerve induces norepinephrine release from the spleen.Efferent vagal nerve stimulation has been shown to stimulate release ofacetylcholine in the celiac-mesenteric ganglia which activatespostsynaptic α7nAChR of the splenic nerve, which in turn leads to therelease of plasma and splenic norepinepherine in the spleen. Splenicnorepinepherine inhibits cytokine production in splenic macrophages. Thevagus nerve innervates the celiac ganglion, the site of origin of thesplenic nerve.

Noradrenergic nerve fibers distribute with the vascular systems andinnervate the perarteriolar lymphatic sheath, the marginal sinus, andthe parafollicular zone. At the marginal sinus, tyrosinehydroxylase-positive fibers run adjacent to macrophages, suggesting adirect correlation between epinephrine release from the nerve terminaland the macrophages associated with them.

There is both structural and functional evidence of a neural reflexpathway between the spleen and the kidneys (the splenorenal neurogenicreflex). Stimulation of the afferent sympathetic nerves of the spleenresults in activation of the efferent sympathetic nerves of kidneys andincreases blood pressure. This reflex is not active after renaldenervation or after administration of Angiotensin II inhibitors,indicating that that the reflex is limited to the splanchnic region anddoes not elicit a general increase in sympathetic nerve activity.

Activation of the Renin-Angiotensin System

Stimulation of the sympathetic nerves of the kidney causes arteriolarvasoconstriction leading to an increase in EPO and renin production, adecrease in GFR, and a decrease in RBF. Renin production leads to theproduction of angiotensin II through the renin-angiotensin system (RAS).Angiotensin II in turn has been found to increases erythropoietinsecretion by reducing renal blood flow and increasing proximal tubularreabsorption (i.e., altering peritubular oxygen tension). Angiotensin IImay also have direct stimulatory effects on bone marrow erythrocyteprecursors. Further angiotensin H has been shown to constrict efferentarterioles of the kidney, while having no effect on the afferentarterioles, leading to renal hyperfiltration and greater GFR.Hyperfiltration can take place in a single nephron even with globallydecreased GFR. In advanced chronic kidney disease, all remainingnephrons hyperfilter.

Activation of RAS is associated with increases in blood pressure andenhanced O₂ ⁻ (oxidative stress) activity, which has been shown to causea reduction of NO availability leading to a disparity between oxidativeand antioxidative mechanisms in the tissues, in turn leading to manypathological states. Angiotensin II stimulates renal release ofsympathetic neurotransmitters, e.g., norepinepherine, which may furtherexacerbate sympathetic overstimulation.

Oxygen Sensing

Oxygen sensing in the kidneys takes place in the juxtamedullary cortexand outer medulla where specialized interstitial cells called renalEpo-producing and oxygen-sensing (REPOS) cells respond to hypoxia(decreased tissue PO₂). Oxygen sensing in the kidney may be affected bychanges in concentration of oxygen, iron, divalent metal ions,ascorbate, reactive oxygen species, tricarboxylic acid cycleintermediates, and nitric oxide (NO).

Renal Blood Flow

Renal blood flow (RBF) is determined by the difference between renalartery pressure and renal vein pressure divided by the total renalvascular resistance. Most of the renal vascular resistance resides inthree major vascular segments: the interlobular arteries, afferentarterioles, and efferent arterioles. Resistance of these vessels isdetermined by the sympathetic nervous system, as well as by varioushormones and a local internal renal control mechanism. If renal arteryand renal vein pressure remain constant, a decrease in vascularresistance in any of the vascular segments increases RBF, while anincrease in resistance tends to reduces RBF.

Input from the sympathetic nervous system triggers vasoconstriction ofthe renal artery and kidney, thereby reducing renal blood flow. Theparasympathetic nervous system inhibits the sympathetic nerves of therenal artery and kidney and trigger vasodilation, thereby increasingrenal blood flow. The sympathetic signals travel through the sympathetictrunk ganglia, where some may synapse, while others synapse at theaorticorenal ganglion and the renal ganglion.

Vasoconstriction of the preglomerular afferent arteriole will decreaseRBF and glomerular filtration. Increasing postglomerular resistance byconstriction of the efferent arteriole, in contrast, augments glomerularfiltration and reduces RBF. Finally, combined vasoconstriction ofafferent and efferent arteriolar dramatically reduces RBF without suchpronounced changes in filtration.

Intense sympathetic nerve stimulation is required to constrict thearterioles and decrease RBF. Under normal conditions, moderate or mildsympathetic nerve stimulation will not have an effect on RBF. Moresubtle increases in renal nerve activity increase renal tubular sodiumreabsorption and increase renin secretion without changes in renalhemodynamics.

The kidneys can endure a relatively large reduction in renal blood flowbefore actual damage to the renal cells occurs. As long as renal bloodflow does not fall below about 20 percent of normal, acute renal failuredue to hypoxia can usually be reversed if the cause of the ischemia iscorrected before damage to the renal cells has occurred. This ischemicstate should not be maintained longer than a few hours to avoidintrarenal acute renal failure.

Under normal conditions, renal blood flow remains relatively constanteven with large fluctuations in arterial blood pressure ranging between80 and 170 mm Hg due to feedback mechanisms intrinsic to the kidney. Thekidneys have a feedback mechanism that links changes in sodium chlorideconcentration at the macula densa with the control of renal arteriolarresistance. The purpose of this feedback mechanism is to ensure arelatively constant delivery of sodium chloride to the distal tubule andprevent spurious fluctuations in renal excretion. The macula densa cellssense fluctuations in sodium chloride concentrations and initiate asignal that both alters the resistance of the afferent arterioles andaffects the release of renin, thereby affecting the resistance of theefferent arterioles.

Chronic Overstimulation of Sympathetic Renal Nerves

The chronic reduction of renal blood flow, increase in GFR (glomerularhyperfiltration), oxidative stress, and inflammatory cytokines, as aresult of overstimulation of the renal sympathetic efferent nerves leadsto loss of renal function as a result of renal ischemia. Loss of renalfunction not only results in the reduction in the number of cellscapable of producing EPO, but also a dampening of the kidney's abilityto sense hypoxic conditions resulting from a lower GFR due to ischemicinjury to renal tubules. Since less oxygen is consumed in the renalcortex due to a lower GFR, the local relative excess of oxygen in therenal cortex results in the down-regulation of EPO production. There isevidence that demonstrates a downward trend toward lower hemoglobinlevels and a reduction in EPO effectiveness or production at lowerlevels of GFR.

Thus sympathetic overstimulation can lead to damage of the kidneys thatresults in both an inability to sense anemia and an inability to produceEPO.

In addition, after chronic overstimulation of the renal sympatheticnervous system, red blood cell production may also be inhibited by theresulting inflammatory response, as discussed above. The inflammatoryresponse may further exacerbates the anemia by, e.g., leading to thesequestration of iron from bone marrow. Chronic kidney disease ischaracterized by elevated circulating levels of inflammatory cytokinessuch as interleukin 6, which can both impair bone marrow function andsignificantly alter iron metabolism.

Nitric Oxide

Nitric oxide (NO) has been shown to induce HIF-1 activation viastabilization of HIF-1α. NO is also a potent vasodilator. NO acts tovasodilate the afferent arterioles. NO is a powerful inhibitor oferyptosis (programmed death of anucleic red cells), Eryptosis isenhanced in a variety of clinical conditions associated with low levelsof nitric oxide, such as heart disease, diabetes, renal insufficiency,sickle-cell anemia, and thalassemia.

Activation of parasympathetic nitrergic nerves (wherein NO mediatestransmission) innervating renal vasculature contributes tovasodilatation in renal arteries and pre- and postglomerular arterioles,an increase in renal blood flow, and a decrease in vascular resistance.NO from neurons in the brain acts on the paraventricular nucleus of thehypothalamus and the rostral ventrolateral medulla and inhibits thecentral sympathetic nerve activity to the kidney, leading to renalvasodilatation and increased renal blood flow.

Under pathological conditions (e.g., during inflammation), high levelsof NO are produced after iNOS (inducible nitric oxide) expression isinduced, mainly in macrophages. But this NO reacts with concomitantlyproduced superoxide anions, thereby generating highly toxic compoundssuch as peroxynitrite and hydroxyl radicals.

The efferent arteriole endothelium contains nNOS (neuronal NO synthase)and eNOS (endothelial NO synthase). The renal nerves found inperivascular connective tissue and near the pelvic epithelium alsocontain nNOS. In addition, there are nNOS-containing neurons insympathetic preganglionic neurons in the spinal cord, Several of thehomeostatic actions of spinal afferents are brought about by the releaseof the transmitters NO and calcitonin gene-related peptide (CORP) fromtheir peripheral endings.

Autonomic Nervous System

Patients with severe autonomic failure have a high incidence of anemia.Up to 38% of these patients are anemic (hemoglobin<120 g/liter for womenand <130 g/liter for men) without an obvious cause. The autonomicnervous system controls the involuntary smooth and cardiac muscles andglands throughout the body, serving the vital organ systems such as theheart and kidneys that function automatically. The two divisions(sympathetic and parasympathetic) of the autonomic nervous system opposeeach other in function, thus maintaining balance. Both pathways includeafferent pathways (from a receptor or an organ to the central nervoussystem) and efferent pathways (acting in the opposite direction) thatrelate to erythropoiesis. Signals transmitted via the parasympatheticfibers of the vagus nerve generate an anti-inflammatory response, whilesignals traveling along the sympathetic fibers initiate erythropoiesisand the inflammatory response.

Under normal physiological conditions, vagal tone (parasympatheticactivation) predominates over sympathetic tone at rest. Abrupt orintense parasympathetic nerve discharge will inhibit tonic sympatheticactivation in dynamic states, such as exercise.

Sympathetic Withdrawal

Sympathetic failure can contribute to anemia by blunting of the expectedcompensatory erythropoietin response. The reticulocyte response to acutebloodletting was greatly diminished in rats when their kidneys werefunctionally denervated. The lack of sympathetic stimulation results indecreased erythropoietin production and development of anemia inpatients with autonomic failure. The magnitude of sympathetic impairmentcorrelates with the severity of anemia.

Overdrive of the Sympathetic Nervous System

Hypertension, heart failure, CHF, advanced cancer, and chronic renaldisease, are a few of many disease states that can result from chronicover-activation of the sympathetic nervous system (SNS) and/or vagalwithdrawal. Chronic activation of the SNS is a maladaptive response thatdrives the progression of these disease states, together with anemia asa common comorbidity. Although EPO production may initially be enhanced,because of the resulting inflammation and/or kidney damage, togetherwith other resulting aggravating factors, anemia often results with theprogression of these disease states. In addition, sympathetic overactivity has been shown to blunt peripheral chemoreceptor function,which in turn increases sympathetic activity.

The Observed/Predicted Ratio

In certain embodiments, the etiology of the anemia is determined bydetermining the EPO observed/predicted (O/P) ratio. The observed EPO maybe determined by quantifying the serum EPO level. The predicted EPOlevel is determined from determining the serum hemoglobin level andcorrelating the observed hemoglobin level with an EPO level that wouldbe normal based on a reference population. An O/P ratio of 1 suggeststhat endogenous EPO production is as expected from the hemoglobin level.A value below 1 suggests that endogenous EPO production is lower thanexpected. A value above 1 suggests that endogenous EPO production ishigher than expected. An O/P<0.916 may be defined as lower thanexpected. An O/P>1.087 may be defined as higher than expected.

Iron-Restricted Erythropoiesis

Chronic inflammation can lead to inefficient iron handling andentrapment in the reticuloendothelial system. Thus in some patients,anemia is caused by the inefficient handling of iron due toinflammation, rather than iron deficiency. In certain embodiments, thepatient's O/P ratio, transferrin saturation, and ferritin levels aredetermined and used to diagnose the etiology of the anemia.Iron-restricted erythropoiesis diagnosed in patients who have high O/Plevels, and low transferrin saturation (e.g., <20%-25%) without veryhigh ferritin (e.g., <1,200 ng/mL).

Patients Having Higher than Expected EPO Levels

Higher than expected EPO levels have been observed in a relatively smallbut significant percentage of anemic CHF patients and are stronglyassociated with a higher mortality compared to anemic CHF patients withexpected or lower than expected EPO levels, independent of hemoglobinlevels.

Higher than expected EPO levels have also been observed as a primaryresponse in patients after intense chemotherapy.

Mechanistically, patients with higher than expected EPO levels arecapable of producing endogenous EPO. It has been shown that serum of CHFpatients inhibits the proliferation of bone marrow derivederythropoietic cells from healthy volunteers, indicating that serumfactors induce insensitivity to endogenous EPO. Such erythropoietinresistance may be due to the pathogenetic triad of iron-restrictederythropoiesis, inflammation, and bone marrow suppression.

Heart Failure

In heart failure (HF) patients, anemia has been found to be due tochronic disease (i.e., unresponsiveness to erythropoietin, due, at leastin part, to chronic inflammation), kidney disease, overstimulation ofthe renin-angiotensin system, hemodiluation, and a deficiency in ironavailable for erythropoiesis.

Erythropoietin plasma levels increase progressively with deterioratingcardiac function in patients with HF. Inflammation appears to be thedominant source of anemia in ischemic HF; neurohormonal factors appearto play the largest role in non-ischemic HF.

Several parameters of cardiac failure have been shown to improve withcorrection of the anemia with subcutaneous erythropoietin in combinationwith iron. Correction of anemia has a major effect on improving cardiacfunction as reflected by an improvement in left ventricular ejectionfraction, a reduction in cardiac dilation and hypertrophy, a reductionin β natriuretic peptide levels, and an increase in oxygen utilizationduring maximal exertion.

Congestive Heart Failure

Endogenous EPO levels are comparable between anemic and nonanemiccongestive heart failure (CHF) patients and are generally elevatedproportional to the severity of symptoms. Sympathetic overactivity maybe triggered or exacerbated by chemoreceptor dysregulation associatedwith fluid and electrolyte shifts associated with CHF. Morespecifically, the renal sympathetic nerves, along with cardiacsympathetic nerves, have been shown to be overstimulated in CHF. Bloodflow to the kidneys has also been shown to decrease. In addition, CHF ischaracterized by an elevation in plasma levels of proinflammatorycytokines, notably IL-6 and TNF-α, while the potentpro-anti-inflammatory cytokines IL-10 has been shown to be reduced.

Stimulation of the renin-angiotensin system as a result of increasedsympathetic stimulation and decreased renal perfusion results in furtherarteriolar vasoconstriction, sodium and water retention, and release ofaldosterone. Release of aldosterone leads to sodium and water retention,endothelial dysfunction, and organ fibrosis. Baroreceptor and osmoticstimuli cause the hypothalamus to release vasopressin. Vasopressincauses reabsorption of water in the renal collecting duct.

Approximately one-third of CHF patients are anemic. Althougherythropoietin levels do not correlate well with hemoglobin levels inmost anemic CHF patients, it has been shown that patients withpersistently high erythropoietin levels had significantly lowerhemoglobin levels. The vast majority (reportedly greater than 90%) ofanemic CHF patients, however, have a significantly low O/P ratio,indicative of an impairment in EPO production. The cause of thisimpairment may be attributed to a combination of decreased renalfunction and a direct inhibition of EPO production by cytokines.

Chronic kidney insufficiency (CKI), which may result from renal ischemiaand inflammation due to prolonged overstimulation of renal sympatheticnerves, is present in about half of all CHF cases and is the most commoncause of anemia in CHF patients. CKI is associated with a lower GFR andthus both EPO production and the ability to sense hypoxia may bedeficient. Fluid retention, and consequently haemodilution, due toactivation of the renin-angiotensin system (RAS), is also a source ofanemia in CHF patients.

While CHF is infrequently associated with biochemical indices ofimpaired iron supply, iron supplies in the bone marrow are oftensignificantly depleted. Hepcidin, a peptide synthesized by the liver, isa key regulator of iron metabolism. Hepcidin is a hormone that lowersserum iron levels and regulates iron transport across membranes,preventing iron from exiting the enterocytes, macrophages, andhepatocytes. The action of hepcidin is mediated by binding to the ironexporter ferroportin. Hepcidin expression in the liver is dependent onthe protein hemojuvelin.

Inflammation leads to increased hepcidin production via IL-6, whereasiron deficiency and factors associated with increased erythropoiesis(hypoxia, bleeding, hemolysis, dyserythropoiesis) suppress theproduction of hepcidin. IL-6 stimulates hepcidin gene transcription,most notably in the hepatocytes. Studies involving human hepatocyteexposure to a panel of cytokines showed that IL-6, but not TNFα or IL-1,induced the production of hepcidin mRNA.

Cancer

Anemia in cancer has been shown to be due to impaired erythropoiesis(production of red blood cells) and relatively inadequate EPOproduction, as evidenced by significantly lower O/P EPO. RAS is known tocontribute to the regulation of tumour growth in several types ofmalignancy. Angiotensin II is a cytokine that acts as a growth factorfor tumors and increases oxidative stress. Angiotensin II type-1 andtype-2 receptors (AT1R and AT2R) are involved in the regulation ofcellular proliferation, angiogenesis, and tumour progression.Angiotensin II levels have been found to be elevated in cancer patients.NO also enables or enhances angiogenesis. Angiogenic growth factors suchas vascular endothelial growth factor (VEGF) and fibroblast growthfactor (FGF) induce NO and require NO to elicit an effect. NO modifiesthe release of cytokines from macrophages. The serum levels of MIF,TNF-α, and IFN-gamma have been found to be significantly higher inanemic cancer patients than those in healthy controls or in nonanemiccancer patients. These inflammatory cytokines, along with others havebeen found to play a major role in the pathophysiology of anemia incancer patients. Inflammatory cytokines and chemokines promote growth oftumor cells, perturb their differentiation, and support the survival ofcancer cells. Down regulation of proinflammatory cytokines, such asTNFα, IL-6 and IL-1k, or transcription factors that are required forsignaling by these cytokines, including NF-kB and STATs, are potentialtargets for both anticancer and anemia therapy.

Cancer, as well as cancer treatments such as chemotherapy, is frequentlyassociated with kidney malfunction and lower GFR. It has been reportedthat between 12% and 49% of critically ill cancer patients experienceacute renal failure and 9% to 32% require renal replacement therapyduring their intensive care unit stay.

Renal Denervation

A bilateral nephrectomy, which inherently includes renal denervation, isknown to reduce blood pressure better than hypertensive medicationcurrently available, and reduce blood pressure even inrefractory/resistant hypertensive patients (patients wherein more thanthree hypertensive medications failed to control blood pressure). See,e.g., Zazgornik, Bilateral Nephrectomy: The Best, but Often OverlookedTreatment for Refractory Hypertension in Hemodialysis Patients (1998),incorporated herein by reference in its entirety. Renal denervation bybilateral nephrectomy is known to affect a cure for hypertension, i.e.,eliminate the patient's dependency of hypertensive medications to lowerblood pressure. Renal denervation by bilateral nephrectomy,splanchnicectomy, and other more drastic sympathectomies is known toreverse cardiovascular diseases, including resulting in reverseremodeling of the heart (wherein the heart becomes healthy again) and adecrease in the likelihood of strokes. Renal denervation, whether bybilateral nephrectomy, intravascular radiofrequency ablation, orlaparoscopic denervation, is known to be safe, i.e., it does not resultin the collateral damage of a more extreme sympathectomy, e.g., asplanchnicectomy wherein patients were found to often suffer fromorthostatic hypotension, arterial hypotension, erectile dysfunction,etc.

Renal denervation by bilateral nephrectomy is known to improve GFR,i.e., kidney function of the transplanted kidneys. Thus a renaldenervation may actually be beneficial to the kidney's inherent abilityto produce EPO. In small, proof-of concept studies in humans, incompleterenal denervation was also shown to stabilize, or at least slow, theprogressive decline of GFR in most subjects, although some patients hada decrease in eGFR of more than a 25% at six months. See, e.g., G.Thomas, et al., Renal denervation to treat resistant hypertension:Guarded optimism, Cleveland Clinic Journal of Medicine, 79(7):501-510(2012): D. Hering, Renal Denervation in Moderate to Severe CKD, JASNASN.2011111062 (2012); G. Simonetti, et al., Endovascular RadiofrequencyRenal Denervation in Treating Refractory Arterial Hypertension: aPreliminary Experience, Radiol Med, 117(3):426-44. (April 2012).Probable mechanisms by which renal denervation exerts thisrenoprotective effect include the blood pressure lowering effect, adecline in the release of renin and adenosine, a resetting of thebaroreceptors, and a decrease in neurogenic inflammation. Hypertensionmay lead to lesions in the kidney. Renin leads to the production ofAngiotensin II which constricts the efferent arterioles of the kidneyand can lead to hyperfiltration. Angiotensin II is also apro-inflammatory. Blockade of A₁ adenosine receptors in the kidney hasbeen shown to maintain GFR and increase renal blood flow. After chronichypertension, the baroreceptors get reset so that the threshold forbaroreceptor activation is at a higher blood pressure, allowing forsympathetic nerve stimulation. Norepinephrine acts on α₁ and α₂adrenergic receptors and proinflammatory neuropeptide substance Pexhibit proinflammatory properties. Proinflammatory cytokines such asTNF-α and IL-1β can either directly reach the central nervous system viathe circulation or alternatively stimulate peripheral afferent nervefibers, thereby activating central neurons in specific brain areas andprobably also autonomic efferent nerves.

However, complete renal denervation, e.g., by a bilateral nephrectomy,in some, but not all patients, results in anemia. Although renaldenervation has been found to diminish response to varying oxygenationand carbon dioxide in kidney transplant patients, i.e., patients havingdenervated kidneys, the renovascular response was not totally abolished.The post-renal transplant patients had a response to hypercapnia (CO₂)that was about 50-55% of the change observed in non-denervated humans.

One study of 15 human patients with stage 3 and 4 chronic kidney disease(mean eGFR 31 mL/min/1.73 m²) subjected to radio frequency intravascularcatheter renal denervation showed a nonsignificant trend towardsincreased hemoglobin levels. Acute renal denervation has not shown toaffect levels of mRNA encoding erythropoietin in animals. ItaloBiaggioni, Erythropoitin in Autonomic Failure, Primer on AutonomicNervous System, Chapter 115, p. 421. This indicates that, in addition torenal nerves, other factors such as circulating catecholamines andneuropeptides also contribute to the renovascular response in humans.

Implantable Body Fluid Analyzer

In an embodiment, an implantable microarray device is used to measurelevels of EPO, nitric oxide, hemoglobin, hepcidin, hemocrit, iron,proinflammatory cytokines, anti-inflammatory cytokines, renin, MIF,CK-MB, cTnT, cTnI, platelets, blood glucose, creatinine, etc. An exampleof such an implantable microarray device suitable for use is disclosedin Koh et al. U.S. Pat. No. 8,192,360, incorporated herein in itsentirety, Koh discloses an exemplary implantable microarray device thatincludes an inlet for a body fluid, a plurality of individual reactioncell arrays where each reaction cell array includes a series of reactioncells configured to receive the body fluid, a sensor array to sense areaction result for an individual reaction cell array where the reactionresult corresponds to a reaction between the body fluid and at least onereagent in each of the reaction cells of the individual reaction cellarray and a positioning mechanism to position an individual reactioncell array with respect to the sensor array.

Determining Renal Insufficiency

In certain embodiments, the level of renal function of the patient ismeasured in order to determine a treatment strategy. In certainembodiments, the level of renal function of the patient is monitored inorder to provide feedback to a neuromodulation device.

Early renal insufficiency (ERI), defined as a calculated or measuredglomerular filtration rate (GFR) between 30 and 60 mL/min per 1.73 m².If the filtering of the kidney is deficient, creatinine blood levelsrise. In certain embodiments, renal dysfunction is defined as a plasmacreatinine>1.5 md/dL.

In an embodiment, the estimated glomerular filtration rate (eGFR) ismeasured using the abbreviated Modification of Diet in Renal Diseaseequation:

eGFR=186.3×(creatinine/88.4)^(−1.154)×(age)^(−0.203)(×0.742 if female).

The estimated prevalence of at least moderate chronic kidney disease(defined as GFR<60 mL/min) in CHF populations is 20% to 40%. Heartfailure and chronic kidney disease may be the result of a maladaptiveresponse that chronically stimulates the sympathetic nervous system.Stimulation of the renal sympathetic nervous system increases therelease of renin, increases sodium reabsorption, and reduces renal bloodflow. In addition, patients suffering from chronic kidney disease mayhave ischemia of the kidneys. Although hypoxia of the kidneys mayinitially result in an increase in EPO, chronic hypoxia has been foundto result in down-regulation of EPO due to resulting proinflammatorycytokines. In certain embodiments, the level of renal function ismeasured in order to determine whether the sympathetic renal nervesshould be stimulated in order to enhance the production of EPO orwhether such stimulation would instead lead to an exacerbation of theanemia. In patients diagnosed with renal insufficiency, vagal nervestimulation in order to decrease systemic inflammation and increase NOproduction may be indicated by the device. In certain embodiments, apatient's vagal nerve is stimulated in order to upregulateanti-inflammatory cytokines and down regulate proinflammatory cytokinesin patients found to have a chronically stimulated sympathetic nervoussystem or ischemic kidneys. In an embodiment, the renal sympatheticnerve is blocked via overstimulation in order to down-regulate theproduction of renin and proinflammatory cytokines.

According to certain embodiments, exogenous EPO may be administeredusing a drug pump, or through conventional administration. In certainembodiments wherein vagal stimulation or sympathetic block are used,less exogenous EPO may be used than otherwise required because of themitigation of inflammation that would otherwise lead to EPOinsensitivity.

Determining Iron Sufficiency

In certain embodiments, the patient's iron level is measured in order todetermine a treatment strategy. In certain embodiments, the patient'siron level is monitored in order to provide feedback to aneuromodulation device.

Iron deficiency may be defined as ferritin<100 mcg/L and/or transferrinsaturation (TSAT)≦20%. The ferritin level indicates the amount of ironstored in the body. In an embodiment, the target ferritin level isgreater than about 100 mcg/L and less than about 800 mcg/L. TSATindicates how much iron is actually available to make red blood cells.In an embodiment, a target TSAT score is between about 15-50% in maleand postmenopausal female subjects and about 12-45% in premenopausalfemale subjects. Target serum iron levels may be between about 65-477μg/dL in males and about 50-170 μg/dL in females. In iron deficientanemia, the serum iron levels are low, while the transferrin levels arehigh, due to the fact that the liver produces more transferrin in theoryto maximize the use of the little iron that is available. In certainembodiments, a drug pump is used to provide adequate iron levels. Incertain embodiments, the device uses the iron levels as an indicationthat vagal nerve stimulation should be used to decrease systemicinflammation.

Determining Vitamin D Sufficiency

In certain embodiments, a vitamin D deficiency is diagnosed when thevitamin D level drops below 20 ng/dL. It has been found that a vitamin Ddeficiency is associated with anemia independent of age, sex,race/ethnicity, with the odds of anemia being increased approximately60% in the presence of vitamin D deficiency. In certain embodiments, adrug pump is used to provide an adequate vitamin D level.

Determining Folic Acid Sufficiency

In certain embodiments, a subject is diagnosed with a folic aciddeficiency when the serum folate is ≦3 μg/L. In an embodiment, a subjectis diagnosed with a folic acid deficiency when the erythrocyte folatelevel is ≦140 μg. In certain embodiments a drug pump is used to providean adequate folic acid level.

Determining Vitamin B12 Sufficiency

In certain embodiments, a subject is diagnosed with a vitamin B12deficiency when the serum level is ≦200 pg/ml. In certain embodiments, asubject is diagnosed with a vitamin B12 deficiency when the serum levelis ≦500 pg/ml. In certain embodiments, a drug pump is used to provide anadequate vitamin B12 level.

Implanted Electrical Nerve Stimulation for Treatment of Anemia

According to certain embodiments, an internal stimulation device is usedfor hemoglobin maintenance in Heart Failure (HF) patients, cancerpatients, patients who have undergone renal denervation, and/or apatient suffering from anemia caused by autonomic imbalance.

Nerve Stimulation

The smooth muscle layers of arteries are controlled by the sympatheticand parasympathetic nervous systems. Typically, the layer of smoothmuscle between elastic lamina of an artery opens and closes the arteriallumen. Closing an arterial lumen is referred to as vasoconstriction andrestricts blood flow; opening an arterial lumen is referred to asvasodilation and facilitates blood flow.

FIG. 1 shows an exemplary stimulation device 100 in electricalcommunication with a patient's heart 102 by way of three leads 104, 106,108, suitable for delivering multi-chamber stimulation and shocktherapy. The leads 104, 106, 108 are optionally configurable fordelivery of stimulation pulses suitable for stimulation of autonomicnerves, non-myocardial tissue, other nerves, etc. In addition, thedevice 100 includes a fourth lead 110 having, in this implementation,three electrodes 144, 144′, 144″ suitable for sensing activity of and/orstimulation of autonomic nerves, non-myocardial tissue, other nerves,etc. For example, this lead may be positioned in and/or near a patient'sheart or near an autonomic nerve within a patient's body and remote fromthe heart. Various examples described herein include positioning a leadproximate to the right and/or the left carotid sinus nerve for at leastpurposes of sensing nerve activity.

The right atrial lead 104, as the name implies, is positioned in and/orpasses through a patient's right atrium. The right atrial lead 104optionally senses atrial cardiac signals and/or provide right atrialchamber stimulation therapy. As shown in FIG. 1, the stimulation device100 is coupled to an implantable right atrial lead 104 having, forexample, an atrial tip electrode 120, which typically is implanted inthe patient's right atrial appendage. The lead 104, as shown in FIG. 1,also includes an atrial ring electrode 121. Of course, the lead 104 mayhave other electrodes as well. For example, the right atrial leadoptionally includes a distal bifurcation having electrodes suitable forsensing activity of and/or stimulating autonomic nerves, non-myocardialtissue, other nerves, etc.

To sense atrial cardiac signals, ventricular cardiac signals and/or toprovide chamber pacing therapy, particularly on the left side of apatient's heart, the stimulation device 100 is coupled to a coronarysinus lead 106 designed for placement in the coronary sinus and/ortributary veins of the coronary sinus. Thus, the coronary sinus lead 106is optionally suitable for positioning at least one distal electrodeadjacent to the left ventricle and/or additional electrode(s) adjacentto the left atrium. In a normal heart, tributary veins of the coronarysinus include, but may not be limited to, the great cardiac vein, theleft marginal vein, the left posterior ventricular vein, the middlecardiac vein, and the small cardiac vein.

Accordingly, an exemplary coronary sinus lead 106 is optionally designedto receive atrial and ventricular cardiac signals and to deliver leftventricular pacing therapy using, for example, at least a leftventricular tip electrode 122, left atrial pacing therapy using at leasta left atrial ring electrode 124, and shocking therapy using at least aleft atrial coil electrode 126. For a complete description of a coronarysinus lead, the reader is directed to U.S. Pat. No. 5,466,254, “CoronarySinus Lead with Atrial Sensing Capability” (Helland), which isincorporated herein by reference. The coronary sinus lead 106 furtheroptionally includes electrodes for stimulation of autonomic nerves. Sucha lead may include pacing and autonomic nerve stimulation functionalityand may further include bifurcations or legs. For example, an exemplarycoronary sinus lead includes pacing electrodes capable of deliveringpacing pulses to a patient's left ventricle and at least one electrodecapable of stimulating an autonomic nerve. An exemplary coronary sinuslead (or left ventricular lead or left atrial lead) may also include atleast one electrode capable of sensing activity of and/or stimulating anautonomic nerve, non-myocardial tissue, other nerves, etc., wherein suchan electrode may be positioned on the lead or a bifurcation or leg ofthe lead.

Stimulation device 100 is also shown in electrical communication withthe patient's heart 102 by way of an implantable right ventricular lead108 having, in this exemplary implementation, a right ventricular tipelectrode 128, a right ventricular ring electrode 130, a rightventricular (RV) coil electrode 132, and an SVC coil electrode 134.Typically, the right ventricular lead 108 is transvenously inserted intothe heart 102 to place the right ventricular tip electrode 128 in theright ventricular apex so that the RV coil electrode 132 will bepositioned in the right ventricle and the SVC coil electrode 134 will bepositioned in the superior vena cava. Accordingly, the right ventricularlead 108 is capable of sensing or receiving cardiac signals, anddelivering stimulation in the form of pacing and shock therapy to theright ventricle. An exemplary right ventricular lead may also include atleast one electrode capable of sensing activity of and/or stimulating anautonomic nerve, non-myocardial tissue, other nerves, etc., wherein suchan electrode may be positioned on the lead or a bifurcation or leg ofthe lead.

The device 100 may be implanted a various locations within the patient.For example, in certain embodiments the stimulation device 100 may beimplanted subcutaneously in the pectoral region of a patient's chest.

The stimulation device 100 may take various forms. For example, incertain embodiments the stimulation device 100 may comprise a dedicatedneurostimulation device.

FIG. 2 shows an exemplary, simplified block diagram depicting variouscomponents of stimulation device 100. The stimulation device 100 can becapable of treating both fast and slow arrhythmias with stimulationtherapy, including cardioversion, defibrillation, and pacingstimulation. The stimulation device can be solely or further capable ofdelivering stimuli to autonomic nerves, non-myocardial tissue, othernerves, etc. While a particular multi-chamber device is shown, it is tobe appreciated and understood that this is done for illustrationpurposes only. Thus, the techniques and methods described below can beimplemented in connection with any suitably configured or configurablestimulation device. Accordingly, one of skill in the art could readilyduplicate, eliminate, or disable the appropriate circuitry in anydesired combination to provide a device capable of treating theappropriate chamber(s) or regions of a patient's heart withcardioversion, defibrillation, pacing stimulation, autonomic nervestimulation, non-myocardial tissue stimulation, other nerve stimulation,etc.

Housing 200 for stimulation device 100 is often referred to as the“can”, “case” or “case electrode”, and may be programmably selected toact as the return electrode for all “unipolar” modes, Housing 200 mayfurther be used as a return electrode alone or in combination with oneor more of the coil electrodes 126, 132 and 134 for shocking purposes.Housing 200 further includes a connector (not shown) having a pluralityof terminals 201, 202, 204, 206, 208, 212, 214, 216, 218, 221 (shownschematically and, for convenience, the names of the electrodes to whichthey are connected are shown next to the terminals).

To achieve right atrial sensing and/or pacing, the connector includes atleast a right atrial tip terminal (A_(R) TIP) 202 adapted for connectionto the atrial tip electrode 120. A right atrial ring terminal (A_(R)RING) 201 is also shown, which is adapted for connection to the atrialring electrode 121. To achieve left chamber sensing, pacing and/orshocking, the connector includes at least a left ventricular tipterminal (V_(L) TIP) 204, a left atrial ring terminal (A_(L) RING) 206,and a left atrial shocking terminal (A_(L) COIL) 208, which are adaptedfor connection to the left ventricular tip electrode 122, the leftatrial ring electrode 124, and the left atrial coil electrode 126,respectively. Connection to suitable autonomic nerve stimulationelectrodes or other tissue stimulation or sensing electrodes is alsopossible via these and/or other terminals (e.g., via a nerve and/ortissue stimulation and/or sensing terminal S ELEC 221)

To support right chamber sensing, pacing, and/or shocking, the connectorfurther includes a right ventricular tip terminal (V_(R) TIP) 212, aright ventricular ring terminal (V_(R) RING) 214, a right ventricularshocking terminal (RV COIL) 216, and a superior vena cava shockingterminal (SVC COIL) 218, which are adapted for connection to the rightventricular tip electrode 128, right ventricular ring electrode 130, theRV coil electrode 132, and the SVC coil electrode 134, respectively.Connection to suitable autonomic nerve stimulation electrodes or othertissue stimulation or sensing electrodes is also possible via theseand/or other terminals (e.g., via a nerve and/or tissue stimulationand/or sensing terminal S ELEC 221).

At the core of the stimulation device 100 is a programmablemicrocontroller 220 that controls the various modes of stimulationtherapy. As is well known in the art, microcontroller 220 typicallyincludes a microprocessor, or equivalent control circuitry, designedspecifically for controlling the delivery of stimulation therapy, andmay further include RAM or ROM memory, logic and timing circuitry, statemachine circuitry, and I/O circuitry. Typically, microcontroller 220includes the ability to process or monitor input signals (data orinformation) as controlled by a program code stored in a designatedblock of memory. The type of microcontroller is not critical to thedescribed implementations. Rather, any suitable microcontroller 220 maybe used that carries out the functions described herein. The use ofmicroprocessor-based control circuits for performing timing and dataanalysis functions are well known in the art.

Representative types of control circuitry that may be used in connectionwith the described embodiments can include the microprocessor-basedcontrol system of U.S. Pat. No. 4,940,052 (Mann et al.), thestate-machine of U.S. Pat. No. 4,712,555 (Thornander et al.) and U.S.Pat. No. 4,944,298 (Sholder), all of which are incorporated by referenceherein. For a more detailed description of the various timing intervalsused within the stimulation device and their inter-relationship, seeU.S. Pat. No. 4,788,980 (Mann et al.), also incorporated herein byreference.

FIG. 2 also shows an atrial pulse generator 222 and a ventricular pulsegenerator 224 that generate pacing stimulation pulses for delivery bythe right atrial lead 104, the coronary sinus lead 106, and/or the rightventricular lead 108 via an electrode configuration switch 226. It isunderstood that in order to provide stimulation therapy in each of thefour chambers of the heart the atrial and ventricular pulse generators,222 and 224, may include dedicated, independent pulse generators,multiplexed pulse generators, or shared pulse generators. The pulsegenerators 222 and 224 are controlled by the microcontroller 220 viaappropriate control signals 228 and 230, respectively, to trigger orinhibit the stimulation pulses.

Microcontroller 220 further includes timing control circuitry 232 tocontrol the timing of the stimulation pulses (e.g., pacing rate,atrio-ventricular (AV) delay, atrial interconduction (A-A) delay, orventricular interconduction (V-V) delay, etc.) as well as to keep trackof the timing of refractory periods, blanking intervals, noise detectionwindows, evoked response windows, alert intervals, marker channeltiming, etc., which is well known in the art.

Microcontroller 220 further includes an arrhythmia detector 234, amorphology discrimination module 236, a capture detection module 237, aCSN module 238 and optionally an orthostatic compensator and a minuteventilation (MV) response module, the latter two are not shown in FIG.2. These components can be utilized by the stimulation device 100 fordetermining desirable times to administer various therapies, includingthose to reduce the effects of orthostatic hypotension. Theaforementioned components may be implemented in hardware as part of themicrocontroller 220, or as software/firmware instructions programmedinto the device and executed on the microcontroller 220 during certainmodes of operation.

The CSN module 238 may perform a variety of tasks related to, forexample, arterial blood chemical composition and/or arterial bloodpressure. This component can be utilized by the stimulation device 100in determining therapy in response to chemosensory and/or barosensoryinformation. The CSN module 238 may be implemented in hardware as partof the microcontroller 220, or as software/firmware instructionsprogrammed into the device and executed on the microcontroller 220during certain modes of operation. The CSN module 238 may optionallyimplement various exemplary methods described herein. The CSN module 238may interact with the physiological sensors 270, the impedance measuringcircuit 278 and optionally other modules. One or more of thephysiological sensors 270 are optionally external to a pulse generatoryet can provide information to the microcontroller 220.

The electronic configuration switch 226 includes a plurality of switchesfor connecting the desired electrodes to the appropriate I/O circuits,thereby providing complete electrode programmability. Accordingly,switch 226, in response to a control signal 242 from the microcontroller220, determines the polarity of the stimulation pulses (e.g., unipolar,bipolar, combipolar, etc.) by selectively closing the appropriatecombination of switches (not shown) as is known in the art.

Atrial sensing circuits 244 and ventricular sensing circuits 246 mayalso be selectively coupled to the right atrial lead 104, coronary sinuslead 106, and the right ventricular lead 108, through the switch 226 fordetecting the presence of cardiac activity in each of the four chambersof the heart. Accordingly, the atrial (ATR. SENSE) and ventricular (VTR.SENSE) sensing circuits, 244 and 246, may include dedicated senseamplifiers, multiplexed amplifiers, or shared amplifiers, Switch 226determines the “sensing polarity” of the cardiac signal by selectivelyclosing the appropriate switches, as is also known in the art. In thisway, the clinician may program the sensing polarity independent of thestimulation polarity. The sensing circuits (e.g., 244 and 246) areoptionally capable of obtaining information indicative of tissuecapture.

Each sensing circuit 244 and 246 preferably employs one or more lowpower, precision amplifiers with programmable gain and/or automatic gaincontrol, bandpass filtering, and a threshold detection circuit, as knownin the art, to selectively sense the cardiac signal of interest. Theautomatic gain control enables the device 100 to deal effectively withthe difficult problem of sensing the low amplitude signalcharacteristics of atrial or ventricular fibrillation.

The outputs of the atrial and ventricular sensing circuits 244 and 246are connected to the microcontroller 220, which, in turn, is able totrigger or inhibit the atrial and ventricular pulse generators 222 and224, respectively, in a demand fashion in response to the absence orpresence of cardiac activity in the appropriate chambers of the heart.Furthermore, as described herein, the microcontroller 220 is alsocapable of analyzing information output from the sensing circuits 244and 246 and/or the data acquisition system 252 to determine or detectwhether capture has occurred and to program a pulse, or pulses, inresponse to such determinations. The sensing circuits 244 and 246, inturn, receive control signals over signal lines 248 and 250 from themicrocontroller 220 for purposes of controlling the gain, threshold,polarization charge removal circuitry (not shown), and the timing of anyblocking circuitry (not shown) coupled to the inputs of the sensingcircuits, 244 and 246, as is known in the art.

For arrhythmia detection, the device 100 utilizes the atrial andventricular sensing circuits, 244 and 246, to sense cardiac signals todetermine whether a rhythm is physiologic or pathologic. In reference toarrhythmias, as used herein, “sensing” is reserved for the noting of anelectrical signal or obtaining data (information), and “detection” isthe processing (analysis) of these sensed signals and noting thepresence of an arrhythmia. The timing intervals between sensed events(e.g., P-waves, R-waves, and depolarization signals associated withfibrillation which are sometimes referred to as “F-waves” or“Fib-waves”) are then classified by the arrhythmia detector 234 of themicrocontroller 220 by comparing them to a predefined rate zone limit(i.e., bradycardia, normal, low rate VT, high rate VT, and fibrillationrate zones) and various other characteristics (e.g., sudden onset,stability, physiologic sensors, and morphology, etc.) in order todetermine the type of remedial therapy that is needed (e.g., bradycardiapacing, anti-tachycardia pacing, cardioversion shocks or defibrillationshocks, collectively referred to as “tiered therapy”).

Cardiac signals are also applied to inputs of an analog-to-digital (ND)data acquisition system 252. The data acquisition system 252 isconfigured to acquire intracardiac electrogram signals, convert the rawanalog data into a digital signal, and store the digital signals forlater processing and/or telemetric transmission to an external device254. The data acquisition system 252 is coupled to the right atrial lead104, the coronary sinus lead 106, the right ventricular lead 108 and/orthe nerve or other tissue stimulation lead 110 through the switch 226 tosample cardiac signals and/or other signals across any pair of desiredelectrodes. The data acquisition system 252 is optionally configured tosense nerve activity and/or muscle activity from muscles other than theheart.

The microcontroller 220 is further coupled to a memory 260 by a suitabledata/address bus 262, wherein the programmable operating parameters usedby the microcontroller 220 are stored and modified, as required, inorder to customize the operation of the stimulation device 100 to suitthe needs of a particular patient. Such operating parameters define, forexample, pacing pulse amplitude, pulse duration, electrode polarity,rate, sensitivity, automatic features, arrhythmia detection criteria,and the amplitude, wave shape, number of pulses, and vector of eachshocking pulse to be delivered to the patient's heart 102 within eachrespective tier of therapy. One feature of the described embodiments isthe ability to sense and store a relatively large amount of data (e.g.,from the data acquisition system 252), which data may then be used forsubsequent analysis to guide the programming of the device.

Advantageously, the operating parameters of the implantable device 100may be non-invasively programmed into the memory 260 through a telemetrycircuit 264 in telemetric communication via communication link 266 withthe external device 254, such as a programmer, transtelephonictransceiver, or a diagnostic system analyzer. The microcontroller 220activates the telemetry circuit 264 with a control signal 268. Thetelemetry circuit 264 advantageously allows intracardiac electrogramsand status information relating to the operation of the device 100 (ascontained in the microcontroller 220 or memory 260) to be sent to theexternal device 254 through an established communication link 266.

As already mentioned, the stimulation device 100 can further include orcommunicate with one or more physiologic sensors 270. The physiologicsensors 270 may be housed within the case 200, on the surface of thecase 200 or external to the case 200. The one or more physiologicsensors optionally connect to the device 100 via one or more of theconnectors or via other connectors. In some instances, a physiologicsensor may communicate with the microcontroller 220 via a wireless link.For example, a wristwatch physiologic sensor may communicate viaelectromagnetic radiation signals or other signals with a circuit in thedevice 100 (e.g., the telemetry circuit 264). Of course, an implantablephysiologic sensor may also communicate with the device 100 via suchcommunication means.

A physiologic sensor may be used to implement “rate-responsive” therapywhere information sensed is used to adjust pacing stimulation rateaccording to, for example, the exercise state of the patient. Aphysiological sensor may be used to sense changes in cardiac output(see, e.g., U.S. Pat. No. 6,314,323, entitled “Heart stimulatordetermining cardiac output, by measuring the systolic pressure, forcontrolling the stimulation”, to Ekwall, issued Nov. 6, 2001, whichdiscusses a pressure sensor adapted to sense pressure in a rightventricle and to generate an electrical pressure signal corresponding tothe sensed pressure, an integrator supplied with the pressure signalwhich integrates the pressure signal between a start time and a stoptime to produce an integration result that corresponds to cardiacoutput), changes in the physiological condition of the heart, or diurnalchanges in activity (e.g., detecting sleep and wake states). Themicrocontroller 220 can respond to such information by adjusting any ofthe various pacing parameters (e.g., rate, AV Delay, V-V Delay, etc.) oranti-arrhythmia therapy parameters (e.g., timing, energy, leading edgevoltage, etc.).

Further examples of physiologic sensors that may be implemented inconjunction with the device 100 include sensors that sense respirationrate, pH of blood, ventricular gradient, oxygen saturation, bloodpressure and so forth. Another sensor that may be used is one thatdetects activity variance, wherein an activity sensor is monitoreddiurnally to detect the low variance in the measurement corresponding tothe sleep state. For a more detailed description of an activity variancesensor, the reader is directed to U.S. Pat. No. 5,476,483 (Bornzin etal.), which patent is hereby incorporated by reference.

The one or more physiologic sensors 270 may optionally include one ormore of components to help detect movement (via, e.g., a position sensoror an accelerometer) and minute ventilation (via an MV sensor) in thepatient. Signals generated by the position sensor and MV sensor may bepassed to the microcontroller 220 for analysis in determining whether toadjust the pacing rate, etc. The microcontroller 220 may thus monitorthe signals for indications of the patient's position and activitystatus, such as whether the patient is climbing up stairs or descendingdown stairs or whether the patient is sitting up after lying down.

The device 100 additionally includes a battery 276 that providesoperating power to all of the circuits shown in FIG. 2. For a device 100which employs shocking therapy, the battery 276 is capable of operatingat low current drains (e.g., preferably less than 10 μA) for longperiods of time, and is capable of providing high-current pulses (forcapacitor charging) when the patient requires a shock pulse (e.g.,preferably, in excess of 2 A, at voltages above 200 V, for periods of 10seconds or more). The battery 276 also desirably has a predictabledischarge characteristic so that elective replacement time can bedetected. Accordingly, the device 100 preferably employs lithium orother suitable battery technology.

As mentioned above, the device 100 may include several components thatprovide functionality relating to neurostimulation as taught herein. Forexample, one or more of the switch 226, the sense circuits 244, 246, andthe data acquisition system 252 may acquire cardiac signals that areused by an IEGM processing component (not shown) to provide IEGM data.This IEGM data may be stored in the data memory 260. In addition, aneuro-signal generator 241 may generate neurostimulation signals astaught herein. Here, the microcontroller 220 may provide one or morecontrol signals 230 to the neuro-signal generator 241 to control thetiming (e.g., start and stop times) and other parameters (e.g.,amplitude, waveshape, and frequency) of the neurostimulation signals.

The microcontroller 220 (e.g., a processor providing signal processingfunctionality) also may implement or support at least a portion of theneurostimulation-related functionality discussed herein. For example, ananemia monitor 240 may perform anemia-related operations as describedabove (e.g., determining whether a anemia condition or a anemiacondition exists). In addition, a neurological stimulation controller239 may perform neurostimulation operations such as, for example,determining which form of innervation to use based on the current anemiccondition and the parameters for the neurostimulation signals.

The exemplary device 100 optionally includes a connector capable ofconnecting a lead that includes a pressure sensor. For example, aconnector (not shown) optionally connects to a pressure sensor capableof receiving information pertaining to chamber pressures or otherpressures. Pressures may be related to cardiac performance and/orrespiration. Pressure information is optionally processed or analyzed bythe neurostimulatory generator module 241.

Commercially available pressure transducers include those marketed byMillar Instruments (Houston, Tex.) under the mark MIKROTIP®. A study byShioi et al., “Rapamycin Attenuates Load-Induced Cardiac Hypertrophy inMice”, Circulation 2003; 107:1664, measured left ventricular pressuresin mice using a Millar pressure transducer inserted through the LV apexand secured in the LV apex with a purse-string suture using 5-0 silk.Various exemplary methods, devices, systems, etc., described hereinoptionally use such a pressure transducer to measure pressures in thebody (e.g., airway, lung, thoracic, chamber of heart, vessel, etc.).

While shown as being included within the stimulation device 100, it isto be understood that the physiologic sensor 270 may also be external tothe stimulation device 100, yet still be implanted within or carried bythe patient. Examples of physiologic sensors that may be implemented indevice 100 include known sensors that, for example, sense pressure,respiration rate, pH of blood, ventricular gradient, cardiac output,preload, afterload, contractility, and so forth. Another sensor that maybe used is one that detects activity variance, wherein an activitysensor is monitored diurnally to detect the low variance in themeasurement corresponding to the sleep state. For a complete descriptionof the activity variance sensor, the reader is directed to U.S. Pat. No.5,476,483 (Bornzin et al), issued Dec. 19, 1995, which patent is herebyincorporated by reference.

More specifically, the physiological sensors 270 optionally includesensors for detecting movement and minute ventilation in the patient.The physiological sensors 270 may include a position sensor and/or aminute ventilation (MV) sensor to sense minute ventilation, which isdefined as the total volume of air that moves in and out of a patient'slungs in a minute. Signals generated by the position sensor and MVsensor are passed to the microcontroller 220 for analysis in determiningwhether to adjust the pacing rate, etc. The microcontroller 220 monitorsthe signals for indications of the patient's position and activitystatus, such as whether the patient is climbing upstairs or descendingdownstairs or whether the patient is sitting up after lying down.

The stimulation device 100 optionally includes circuitry capable ofsensing heart sounds and/or vibration associated with events thatproduce heart sounds. Such circuitry may include an accelerometer asconventionally used for patient position and/or activity determinations.Accelerometers typically include two or three sensors aligned alongorthogonal axes. For example, a commercially availablemicro-electromechanical system (MEMS) marketed as the ADXL202 by AnalogDevices, Inc. (Norwood, Mass.) has a mass of about 5 grams and a 14 leadCERPAK (approx. 10 mm by 10 mm by 5 mm or a volume of approx. 500 mm³).The ADXL202 MEMS is a dual-axis accelerometer on a single monolithicintegrated circuit and includes polysilicon springs that provide aresistance against acceleration forces. The term MEMS has been definedgenerally as a system or device having micro-circuitry on a tiny siliconchip into which some mechanical device such as a mirror or a sensor hasbeen manufactured. The aforementioned ADXL202 MEMS includesmicro-circuitry and a mechanical oscillator.

While an accelerometer may be included in the case of an implantablepulse generator device, alternatively, an accelerometer communicateswith such a device via a lead or through electrical signals conducted bybody tissue and/or fluid. In the latter instance, the accelerometer maybe positioned to advantageously sense vibrations associated with cardiacevents. For example, an epicardial accelerometer may have improvedsignal to noise for cardiac events compared to an accelerometer housedin a case of an implanted pulse generator device.

The stimulation device 100 can further include magnet detectioncircuitry (not shown), coupled to the microcontroller 220, to detectwhen a magnet is placed over the stimulation device 100. A magnet may beused by a clinician to perform various test functions of the stimulationdevice 100 and/or to signal the microcontroller 220 that the externalprogrammer 254 is in place to receive or transmit data to themicrocontroller 220 through the telemetry circuits 264. Trigger IEGMstorage also can be achieved by magnet.

The stimulation device 100 further includes an impedance measuringcircuit 278 that is enabled by the microcontroller 220 via a controlsignal 280. The known uses for an impedance measuring circuit 278include, but are not limited to, lead impedance surveillance during theacute and chronic phases for proper lead positioning or dislodgement;detecting operable electrodes and automatically switching to an operablepair if dislodgement occurs; measuring respiration or minuteventilation; measuring thoracic impedance for determining shockthresholds (HF indications—pulmonary edema and other factors); detectingwhen the device has been implanted; measuring stroke volume; anddetecting the opening of heart valves, etc. The impedance measuringcircuit 278 is advantageously coupled to the switch 226 so that anydesired electrode may be used.

In the case where the stimulation device 100 is intended to operate asan implantable cardioverter/defibrillator (ICD) device, it detects theoccurrence of an arrhythmia, and automatically applies an appropriatetherapy to the heart aimed at terminating the detected arrhythmia. Tothis end, the microcontroller 220 further controls a shocking circuit282 by way of a control signal 284. The shocking circuit 282 generatesshocking pulses in a range of joules, for example, conventionally up toabout 40 J, as controlled by the microcontroller 220. Such shockingpulses are applied to the patient's heart 102 through at least twoshocking electrodes, and as shown in this embodiment, selected from theleft atrial coil electrode 126, the RV coil electrode 132, and/or theSVC coil electrode 134. As noted above, the housing 200 may act as anactive electrode in combination with the RV electrode 132, or as part ofa split electrical vector using the SVC coil electrode 134 or the leftatrial coil electrode 126 (i.e., using the RV electrode as a commonelectrode).

Cardioversion level shocks are generally considered to be of low tomoderate energy level (so as to minimize pain felt by the patient),and/or synchronized with an R-wave and/or pertaining to the treatment oftachycardia. Defibrillation shocks are generally of moderate to highenergy level (i.e., corresponding to thresholds in the range ofapproximately 5 J to approximately 40 J), delivered asynchronously(since R-waves may be too disorganized), and pertaining exclusively tothe treatment of fibrillation. Accordingly, the microcontroller 220 iscapable of controlling the synchronous or asynchronous delivery of theshocking pulses.

In low-energy cardioversion, an ICD device typically delivers acardioversion stimulus (e.g., 0.1 J, etc.) synchronously with a QRScomplex; thus, avoiding the vulnerable period of the T wave and avoidingan increased risk of initiation of VF. In general, if antitachycardiapacing or cardioversion fails to terminate a tachycardia, then, forexample, after a programmed time interval or if the tachycardiaaccelerates, the ICD device initiates defibrillation therapy.

While an ICD device may reserve defibrillation as a latter tier therapy,it may use defibrillation as a first-tier therapy for VF. In general, anICD device does not synchronize defibrillation therapy with any givenportion of a ECG. Again, defibrillation therapy typically involveshigh-energy shocks (e.g., 5 J to 40 J), which can include monophasic orunidirectional and/or biphasic or bidirectional shock waveforms.Defibrillation may also include delivery of pulses over two currentpathways.

Renal Nerve Modulation

The primary stimulus for increased EPO synthesis is tissue hypoxiacaused by decreased blood oxygen availability. This hypoxia signal isreceived primarily in the kidney, which responds by increasingproduction and secretion of EPO. The EPO is transported to the bonemarrow where it promotes proliferation and differentiation of red cells.As a result of this increased red cell production, the blood's oxygencarrying capacity increases, the stimulus of hypoxia is reduced, and EPOproduction is decreased to maintain a steady state.

In use, the lead 110 may be delivered to a renal vessel in proximity toneural tissue contributing to renal function, as explained in furtherdetail below. The renal vessel may be a renal artery, vein or othervessel. In an embodiment, O₂ perfusion in the kidney is modulated tocause EPO release. According to this embodiment, sympathetic nerves ofthe kidney can be stimulated in order to decrease renal blood flow anddecrease GFR by vasoconstriction of the renal arteries. The kidney cellsthat make EPO are specialized and are sensitive to low oxygen levels inthe blood. These cells release EPO when the oxygen level is low in thekidney. EPO then stimulates the bone marrow to produce more red cellsand thereby increase the oxygen-carrying capacity of the blood. Hypoxiaand anemia are the fundamental stimulus for erythropoietin (EPO)production. Recent in vitro studies suggest that EPO secretion inresponse to hypoxia is regulated by adenosine in the kidney.Extracellular adenosine is derived mainly from phosphohydroiysis ofadenosine 5_-onophosphate (AMP). Ecto-5_-nucleotidase (CD73), aubiquitously expressed glycosyl phosphatidylinositol-anchoredectoenzyme, is the pacemaker of this reaction. Because of itstranscriptional induction by hypoxia, CD73-dependent adenosinegeneration is particularly prominent during conditions of limited oxygenavailability. Furthermore, recent studies have shown that theEPO-producing peritubular renal fibroblasts express high amounts ofecto-5-nucleotidase on their surface.

Methods of radiofrequency catheter ablation are described in U.S.Publication Nos. 2013/0218029, 2013/0085489, 201310245621, 2013/0090637,2011/0118726, and 2011/0137298, each of which is incorporated herein byreference in its entirety, In certain embodiments, these ablationcatheters are modified in order to provide renal nerve stimulation,either in addition to or as a substitute for ablation, U.S. PublicationNos. 2012/0290053 and 2012/0290024, each of which is incorporated hereinby reference in its entirety, describe renal nerve modulation systemsfor treatment of hypertension that can be modified in accordance withcertain embodiments in order to stimulate the production of EPO.

FIG. 3A is a perspective view of a neurological lead 310 configured tostimulate EPO production. According to this embodiment, a neurologicallead 310 includes an elongated catheter body 312 extendinglongitudinally between a proximal end (not shown) which connects to theneurological lead 310 and a distal end 314 along a longitudinal axis316. A neuromodulation element assembly 320 includes a plurality ofelectrodes 322 connected to the catheter body 312. The electrodes 322are discretely spaced from each other longitudinally and/or laterally.In certain embodiments, at least two of the electrodes 322 are spacedfrom one another longitudinally. In certain embodiments, the electrodes322 are not spaced from one another longitudinally.

In certain embodiments, the electrodes 322 are configured for modulation(inhibition or stimulation) of the renal nerves, and/or to sense. Theneuromodulation element assembly 320 can be configured to unipolar,bipolar, or multi-polar modulation. The modulation electrodes can bemade of platinum-iridium (Ptir) or some other suitable electrodematerials. Examples of sensing electrodes include sensors for sensingtemperature, oxygen in blood, catheter tip force or pressure, bloodpressure, blood flow, nerve activity, and impedance contact with therenal vein near the modulation electrode. The neuromodulation elementassembly 320 has a terminal connector at the proximal end which isconnected to a pulse generator. The neuromodulation element assembly 320is preformed for fixation in the renal artery and/or vein and to achievegood electrode-tissue contact. Because the renal blood vessels (veinsand arteries) are subject to displacement during respiration, theneuromodulation element assembly 320 includes a passive or an activefixation mechanism for fixation in the renal blood vessel. Theneuromodulation element assembly 320 can utilize a variety of fixationmechanisms, different conductor designs, and different cross-sectionalconfigurations.

As seen in FIG. 3A, the neuromodulation element assembly 320 may includea plurality of spines 324, which may be oriented generallylongitudinally. Each spine 324 has a proximal end 326 connected to thecatheter body 312 and a distal end 328. The distal ends 328 of thespines 324 are connected to a spine distal junction 330. Each spine 324includes an intermediate segment 332, a proximal stiffness changebetween the proximal end 326 and the intermediate segment 332 of thespine 324, and a distal stiffness change between the distal end 328 andthe intermediate segment 332 of the spine 324. The spines 324 include aplurality of electrodes 322 on the intermediate segments 332.

FIG. 3B illustrates an alternative embodiment, wherein theneuromodulation element assembly 320 has a helical configuration. Ahelix, sometimes also called a coil, is a curve for which the tangentmakes a constant angle with a fixed line. The shortest path between twopoints on a cylinder (one not directly above the other) is a fractionalturn of a helix (e.g., consider the paths taken by squirrels chasing oneanother up and around tree trunks). Helices come in enantiomorphousleft- (coils counterclockwise as it “goes away”) and right-handed forms(coils clockwise).

A helix is a space curve with parametric equations: x=r*cos(t);y=r*sin(t); and z=c*t, for t within a range of 0 to 2π, where r is theradius of the helix and c is a constant giving the vertical separationof the helix's loops. Other equations exist to describe arc length,torsion, etc. Other possible configurations include, for example,sinusoidal or S-shaped, conical spirals, Poinsot's spirals, polygonalspirals, spherical spirals, semi-spherical spirals, slinky (e.g., spiralwound around a helix), stent-like, running or serial loop, etc.

In FIG. 3B the neuromodulation element assembly 320 includes a helicalconfiguration that includes three electrodes 322 a, 322 b, and 322 c.Such a neuromodulation element assembly 320 may include one or moreelectrodes. Such electrodes may act as anodes or cathodes. In general,the configuration acts to help secure the neuromodulation elementassembly 320 at a particular location, for example, in an artery orvein.

Carotid Body and Sinus Stimulation

Various exemplary techniques described herein relate to the carotid bodyand the carotid sinus, U.S. Pat. No. 8,326,429, incorporated herein byreference in its entirety, describes therapeutic actions that may treatconditions such as sleep apnea, an increase in metabolic demand,hypoglycemia, hypertension, renal failure, and congestive heart failure.The carotid body is a small cluster of chemoreceptors and supportingcells located near the bifurcation of the carotid artery. It responds tochanges in the composition of arterial blood, including the partialpressures of oxygen and carbon dioxide as well as pH, temperature andpotassium concentration. The chemoreceptors responsible for sensingchanges in blood gasses are called glomus cells. The carotid body isinvolved in both respiratory and cardiovascular control through complexneural pathways, for example, the carotid body provides for a reflexadjustment of respiration according to arterial blood chemistry. Hypoxia(decrease in PO₂), hypercapnia (increase in PCO₂), and acidosis(decrease in pH) increase the rate of chemosensory discharges in thecarotid sinus nerve (CSN) and initiate ventilatory and cardiovascularreflex adjustments.

More specifically, the carotid body responds to a decrease in PaO₂(e.g., atrial hypoxia), ischemia (e.g., from hypotension), an increasein PCO₂ (e.g., >10 mmHg), a decrease in pH (e.g., >about 0.1 to about0.2 pH units), metabolic poisons (e.g., cyanide), drugs (e.g., nicotine,lobeline) and a decrease in blood glucose concentration.

While mechanisms underlying communication between glomus cells of thecarotid body and petrosal ganglion neurons are not completely known,glomus cells, in response to natural and pharmacological stimuli, areexpected to release at least one excitatory transmitter that generatesdischarges in the sensory nerve terminals of petrosal ganglion (PG)neurons.

The carotid sinus is a small oval bulge at the commencement of theinternal carotid artery. At the carotid sinus, the arterial wall is thinand has a rich nerve supply from CN IX as well as some innervation fromCN X. These nerves form an afferent limb of baroreceptor reflex changesin heart rate and blood pressure.

The regulation of arterial blood pressure involves negative feedbacksystems incorporating baroreceptors located in the carotid sinus and inthe aortic arch. The carotid sinus nerve (CSN) branch of CN IXinnervates the carotid sinus, which synapses in the brainstem. Theaortic arch baroreceptors are innervated by the aortic nerve, which thencombines with the vagus nerve (X cranial nerve) traveling to thebrainstem. Arterial baroreceptors are sensitive to stretching of thewalls of the vessels in which the nerve endings lie. Increasedstretching augments the firing rate of the receptors and nerves, andrecruits additional afferent nerves. The receptors of the carotid sinusrespond to pressures ranging from about 60 mm Hg to about 180 mmHg.

A branch of CN IX innervates baroreceptors of the carotid sinus andchemoreceptors of the carotid body. This branch includes two sets ofafferent fibers. One set ramifies in the wall of the carotid sinus (atthe commencement of the internal carotid artery), terminating in stretchreceptors responsive to systolic blood pressure: these baroreceptorneurons terminate centrally in the medial part of the nucleussolitarius. The second set of afferents in the carotid branch suppliesglomus cells in the carotid body. These nerve endings are chemoreceptorsmonitoring blood chemistry. The central terminals enter the dorsalrespiratory nucleus. More generally, the nerve supply to the carotidsinus and body is derived from the carotid branch of CN IX, branches tothe carotid body from the inferior ganglion of CN X and sympatheticbranches from the superior cervical ganglion.

Afferent nerve activity of CN IX due to a change in blood pressure, adecrease in blood oxygen concentration, a decrease in blood pH, and/oran increase in blood carbon dioxide concentration can cause correctivechanges in ventilation so as to maintain blood gas and pH homeostasis.

Stimulation of the carotid chemoreceptors via hypoxic conditions hasbeen found to affect renal hemodynamics. Hypoxia increases efferentrenal activity and produces renal vasoconstriction.

FIG. 4 shows an exemplary arrangement 410 of electrodes that can be usedfor both neuromodulation and sensing. The arrangement 410 is shown withreference to the heart, the brain, the aorta, the right common carotidartery and bifurcation, the left common carotid artery and bifurcation,the right carotid body and sinus (CB-CS_(R)), the left carotid body andsinus (CB-CS_(L)), and the ninth and tenth cranial nerves. The carotidarteries carry blood to the brain and innervation of the carotid bodyand sinus, which are located near the brain, allow the body to monitorblood flow and blood chemistry and respond accordingly. The tenthcranial nerve (CN X) is the vagus nerve and is primarily associated withparasympathetic activity. The vagus includes the right vagus (X_(R)) andthe left vagus (X_(L)). Various studies indicate that the vagus mayinnervate the carotid body while vagal innervation of the aorticbaroreceptors is well established.

The arrangement 410 includes the implantable device 100 and aneuromodulation lead 110. The lead 110 includes one or more electrodes144, 144′ and may include a bifurcation that allows at least oneelectrode to be positioned at, or proximate to, each CSN. In the exampleof FIG. 4, the lead 110 includes a bifurcation where one branch of thelead allows for positioning the electrode 144′ at the right CSN(CSN_(R))and another branch of the lead allows for positioning the electrode 144at the left CSN(CSN_(L)).

FIG. 5 shows a more detailed diagram of a cell unit of the carotid body500 and a block diagram of a process 510. Sustentacular cells (modifiedSchwann cells, labeled SC) are intimately surrounded and interlaced witharch network of capillaries and venules. Clusters of cells are called“zellballen”, and can generally be separated into “light” cell (labeledLC) and “dark” cell (labeled DC) subpopulations, referring to thedensity of intracellular neurosecretory granules. Chief cells aremembers of the amine precursor and uptake decarboxylase (APUD) family,recently referred to as the DNS (diffuse neuroendocrine system).

In an embodiment, a cell unit of a carotid body generates afferent nerveactivity in response to a neuromodulation signal. For example, aneuromodulation signal in the process 510 can mimic a decrease in oxygenconcentration, a decrease in pH and/or an increase in carbon dioxide,causing cells of the unit to release dopamine, which increases CSNactivity and provokes centrally-mediated cardiopulmonary responses.

Spleen Stimulation

In certain embodiments, the spleen is electrically stimulated to releasestored red cells to generate circulating signaling mechanisms of redcell shortage. Inhibitory or excitatory stimulation of the spleen'sautonomic nerves would modulate blood flow to the organ, as well ascontrol smooth muscle that maintains a small reserve of erythrocytes inthe spleen. In certain embodiment, the spleen is electrically stimulatedto vasoconstrict, reducing the flow of blood and lymph in an effort toblock eryptosis.

Spinal Cord Stimulation

Renal sympathetic neurons originate in the thoracic and lumbar portionof the spinal cord (generally the area of T10-L1), and the ganglia aresituated close to the spinal cord. In an embodiment, pre-ganglionicefferent nerves in the spinal cord in the area of T10-L1 areelectrically stimulated. The pre-ganglionic efferent nerves communicateeventually to the kidney, or stimulate post-ganglionic nerves either atthe appropriate sympathetic ganglia or nearer to the kidney. Thisstimulation is done to cause vasoconstriction in the arteries of thekidney, for temporary therapeutic reduction in renal blood flow. Theeffect is reduced oxygen delivery to the kidney. In an embodiment, thepre-ganglionic efferent nerves are stimulated intermittently and atappropriate time scale in order to create temporary hypoxia, therebyencouraging EPO production without causing ischemic injury,hypertension, or retention of waste products. In an embodiment,Angiotensin II receptor blockade is applied to prevent chronic bloodpressure elevation and inflammation from intermittent hypoxia.

Brain Stimulation

Signals effecting erythropoiesis are generated in the hypothalamus andmedulla oblongata within the brain. Electrical stimulation of thehypothalamic complex has been reported to induce increase in the numberof circulating erythrocytes and reticulocytes, and in the hemoglobinlevels. The diencephalon exerts its effect on anterior pituitaryhormones through secretion of some neuroumoral substances transmitted tothe hypophyseal cells by mean of the hupophysceal portal circulation.Stimulation of the hypothalamus has also been found to upregulatecytokine production. According to certain embodiments, the NF-κB pathwayin the hypothalamus is blocked to reduce inflammation. In an embodiment,controlled hypothalamic deep brain stimulation is used to allow forregulation of erythropoiesis.

U.S. Pat. No. 6,978,180, incorporated herein by reference in itsentirety, describes a neurological stimulation system adapted forimplantation into a person's body for electrical, chemical, or combinedelectrical and chemical stimulation of target nerve tissue in theperson's brain stem, that can be used in certain embodiments to increaseEPO production and/or treat anemia. U.S. Pat. No. 7,313,442,incorporated herein by reference in its entirety, describes method and asystem for using electrical stimulation and/or chemical stimulation thatare used according to certain embodiments to stimulate, for example thehypothalamus. For electrical stimulation, the system includes anelectrical stimulation lead adapted for implantation on, in, or near thebrain stem, and including electrodes adapted to be positioned on, in, ornear target nerve tissue in the brain stem, for delivering electricalstimulation energy to the target nerve tissue. For chemical stimulation,the system includes an infusion catheter adapted for implantation on,in, or near the brain stem, and including openings adapted to bepositioned on, in, or near target nerve tissue in the brain stem, fordelivering a chemical to the target nerve tissue. The system alsoincludes a stimulation source adapted for implantation in the person'sbody and operable to generate pulses of electrical stimulation energy orpulses of the chemical, for delivery to the target nerve tissue in thebrain stem.

A predetermined brain region can be indirectly stimulated by implantinga stimulation lead in communication with a cranial nerve (e.g. olfactorynerve, optic, nerve, oculomoter nerve, trochlear nerve, trigeminalnerve, abducent nerve, facial nerve, vestibulocochlear nerve,glossopharyngeal nerve, vagal nerve, accessory nerve, and thehypoglossal nerve) as well as high cervical nerves (cervical nerves haveanastomoses with lower cranial nerves) such that stimulation of acranial nerve indirectly stimulates the predetermined brain region. Suchtechniques are further described in U.S. Pat. No. 7,734,340, U.S. Pat.Nos. 6,721,603; 6,622,047; and 5,335,657, and U.S. ProvisionalApplication 60/591,195 entitled “Stimulation System and Method forTreating a Neurological Disorder” each of which are incorporated hereinby reference.

Peripheral Nervous System Stimulation

Mechanisms of red cell death could also be inhibited. In an embodiment,electrical stimulation is used to alter autonomic tone of blood vesselsthat perfuse the bone marrow where erythrocytes are formed to promotelarger red cells that would have greater hemoglobin-carrying capacityand longer lifetime.

Peripheral vasodilation may also be used to change systemic oxygendemand for hypoxic stimulation of erythropoietin production.

A neurological lead may be implanted adjacent to one or more nerves ofthe peripheral nervous system of the patient. In an embodiment, systemicoxygen demand is changed to affect hypoxic stimulation of erythropoietinproduction by causing peripheral vasodilation and renalvasoconstriction.

Determining Autonomic Tone

In certain embodiments, autonomic tone is measured in order to determinea treatment strategy and/or to provide feedback as to the effectivenessof the treatment strategy. Stimulation of EPO through the sympatheticnervous system, as described above; may not be appropriate under certaincircumstances where a patient's anemia is found to be caused by vagalwithdrawal, rather than an inability to create EPO. In certainembodiments, neurostimulation to invoke autonomic balance is performedprior to, or in lieu of sympathetic EPO stimulation. In certainembodiments, autonomic tone is monitored in order to provide feedback toa neuromodulation device for treatment of anemia.

U.S. Pat. No. 7,711,415, incorporated herein by reference in itsentirety, describes exemplary implantable devices capable ofindependently monitoring sympathetic and parasympathetic influences onthe heart. This can be accomplished, for example, by using one or moreprocessors to assess the level of parasympathetic tone in one of thefollowing manners: determining the patient's diurnal variation ofcardiac intervals based on the measured cardiac intervals, and assessingthe level of parasympathetic tone based on the diurnal variation ofcardiac intervals; determining the patient's diurnal variation of heartrate based on the measured cardiac intervals, and assessing the level ofparasympathetic tone based on the diurnal variation of heart rate; andidentifying each said cardiac interval that is longer than theimmediately preceding cardiac interval as being indicative of cardiacdeceleration, and assessing the level of parasympathetic tone based onthe cardiac intervals that are identified as being indicative of cardiacdeceleration.

The one or more processor may assess the level of sympathetic tone inone of the following manners: by determining the patient's averagecardiac interval based on the measured cardiac intervals, and assessingthe level of sympathetic tone based on the determined average cardiacinterval; by determining the patient's average heart rate based on themeasured cardiac intervals, and assessing the level of sympathetic tonebased on the determined average heart rate; and by identifying each saidcardiac interval that is shorter than the immediately preceding cardiacinterval as being indicative of cardiac acceleration, and assessing thelevel of sympathetic tone based on the cardiac intervals that areidentified as being indicative of cardiac acceleration.

Autonomic tone of the patient can also be monitored usingphoto-plethysmography (PPG), as described in U.S. Pat. No. 7,177,686,entitled “Using Photo-Plethysmography to Monitor Autonomic Tone andPerforming Pacing Optimization based on Monitored Autonomic Tone,” filedJan. 23, 2004, which is incorporated herein by reference in itsentirety. This can be accomplished, for example, by incorporating alight source and light detector into the same implantable stimulationdevice that is used for pacing, as is described in detail in theapplication just incorporated by reference, as well as in U.S. Pat. Nos.6,591,639 and 6,40,675, which are also incorporated herein by referencein their entirety. Changes in autonomic tone then can be monitored basedon changes in pulse amplitude associated with a PPG signal that isproduced using the light source and light detector. For example, thiscan include: recognizing an increase in pulse amplitude as a decrease inthe sympathetic tone of the patient; recognizing an increase in pulseamplitude variability as a decrease in the sympathetic tone of thepatient; recognizing a decrease in pulse amplitude as an increase in thesympathetic tone of the patient; and/or recognizing a decrease in pulseamplitude variability as an increase in the sympathetic tone of thepatient. This may also include: recognizing an increase in pulseamplitude as an increase in the parasympathetic tone of the patient;recognizing an increase in pulse amplitude variability as an increase inthe parasympathetic tone of the patient; recognizing a decrease in pulseamplitude as a decrease in the parasympathetic tone of the patient;and/or recognizing a decrease in pulse amplitude variability as adecrease in the parasympathetic tone of the patient. Various thresholdscan be defined to distinguish between the different levels of autonomictone, which can include extremely sympathetic, predominantlysympathetic, neutral, predominately parasympathetic and extremelyparasympathetic.

Parasympathetic (i.e., vagal) activity is the major contributor to thehigh-frequency (HF, 0.15-0.4 Hz) components of HRV, while both vagal andsympathetic activities contribute to its low-frequency (LF, 0.04-0.15Hz) components. Thus the power of HRV in the HF band has widely beenused to quantitatively describe vagal activity and the ratio of LF to HFspectral powers have been utilized as a broad index of “sympathovagalbalance”.

Other schemes for monitoring autonomic tone, e.g., via the well-knowntechnique of heart rate variability, are also within the spirit andscope of the present disclosure. In such techniques, a measure ofsympathovagal balance is often given in terms of some form of standarddeviation in RR intervals (e.g., SDNN, a time domain approach) or ratioof low to high frequency components of the power spectrum (the spectralapproach).

More specifically, in one time domain approach, the standard deviationof RR intervals (SDNN) is measured. In this approach, an increase inSDNN is interpreted as an increased predominance of the sympatheticcomponent (and a proportional decrease in the parasympatheticcomponent), where a decrease in the SDNN is interpreted as an increasedpredominance of the parasympathetic component (and a proportionaldecrease in the parasympathetic component).

In one spectral approach, measures of normal RR intervals are convertedinto the frequency-domain so that its spectral frequency components canbe analyzed. Two frequency bands are indicated as being of interest,including, e.g., a low frequency (LF) band (e.g., between 0.04 Hz and0.14 Hz) and a high frequency (HF) band (e.g., between 0.15 Hz. and 0.40Hz). The HF band of the R-R interval signal is believed to be isinfluenced by only the parasympathetic component of the autonomicnervous system. The LF band of the R-R interval signal is believed to beinfluenced by both the sympathetic and parasympathetic components of theautonomic nervous system, Consequently, the ratio LF/HF is used as anindication of the autonomic balance between sympathetic andparasympathetic components of the autonomic nervous system. Morespecifically, an increase in the LF/HF ratio is interpreted as anincreased predominance of the sympathetic component (and a proportionaldecrease in the parasympathetic component), where a decrease in theLF/HF ratio is interpreted as an increased predominance of theparasympathetic component (and a proportional decrease in theparasympathetic component).

A related time domain approach obtains a first measure that is believedto be influenced by only the parasympathetic component of the autonomicnervous system, and a second measure that is believed to be influencedby both the sympathetic and parasympathetic components of the autonomicnervous system. As in the above described spectral approach, a ratio isthen taken of the two measures to obtain a measure of the autonomicbalance between sympathetic and parasympathetic components of theautonomic nervous system. Similarly, an increase in the ratio isinterpreted as an increased predominance of the sympathetic component(and a proportional decrease in the parasympathetic component), where adecrease in the ratio is interpreted as an increased predominance of theparasympathetic component (and a proportional decrease in theparasympathetic component).

Sympathetic activity may also be detected using microneurography(efferent post-ganglionic muscle sympathetic nerve activity, MSNA) andregional norepinephrine spillover technique. In microneurography, asolid tungsten microelectrode or a concentric electrode with an outerdiameter of only 200 micrometers is inserted percutaneously andpositioned intraneurally. The very small surface of the active recordingelectrode is brought in intimate contact with nerve fibers within anindividual nerve fascicle, while the reference electrode surface ispositioned nearby, thereby permitting the recording of anelectroneurogram of electrically induced nerve responses derived fromthe entire nerve fiber spectrum, i.e. from both thick and thinmyelinated fibers and from thin, unmyelinated fibers, having diametersbetween 20-1 micrometers and conduction velocities between 70-1 msec.MSNA measurements are described in Tulppo M P et al. Physiologicalbackground of the loss of fractal heart rate dynamics. Circulation, July19; 112(3):314-9, 2005, incorporated herein by reference.

Blood pressure variability (BPV) and baroreflex function (baroreceptorsensitivity, BRS) may also be measured in accordance with well-knownprocedures in the art and used to assess autonomic balance. BRS indicescorrelate negatively with BPV and positively with HRV.

Complex demodulation (CDM) is a method for analyzing heart rate andreveals instantaneous dynamic changes in heart rate and blood pressurethat are not revealed by the standard spectral methods. COM is discussedin Shin et al., “Assessment of autonomic regulation of heart ratevariability by the method of complex demodulation,” IEEE Transactions onBiomedical Engineering, vol. 36, No. 2, February 1989, which isincorporated herein by reference.

Neurostimulation to Maintain Sympathetic/Parasympathetic Balance

In an embodiment a neuromodulation system is used in patientsdemonstrating severe autonomic failure for maintenance of sympatheticbalance, which would secondarily maintain the expected compensatoryerythropoietin response. U.S. Pat. No. 6,937,896 (“Kroll”), incorporatedherein by reference in its entirety, describes methods and systems forstimulating the intrinsic nervous system of the heart to allow formaintenance of sympathetic balance. In certain embodiments, the Krollsystem is modified to provide for maintenance of the expectedcompensatory erythropoietin response. Heart rate variability basedcontinuous detection of the underlying sympathetic and parasympatheticsystem and balance thereof will be used as a closed loop system todetect and then stimulate to provide autonomic balance. Systemicinflammation may be alleviated by restoring autonomic balance, which maysecondarily relieve the patient's anemia.

Parasympathetic activity may be increased to restore autonomic balanceby electrically stimulating the fibers of the cranial nerve X, known asvagus nerve, transvenously by means of an endovascular electrodeimplanted in, for example, the superior vena cava. U.S. Pat. Nos.7,813,805 and 8,473,068, incorporated herein by reference in itsentirety, describe subcardiac threshold vagal nerves stimulationapparatuses suitable for use in certain embodiments. US Publication No.2010/0114227, incorporated herein by reference in its entirety, vagalnerves stimulation apparatuses suitable for use in certain embodiments.

Sympathetic Deficiency

In certain embodiments, for patients demonstrating a deficiency in thesympathetic nervous system, stimulation of the renal nerves can be usedto increase EPO production.

Determining State of Inflammation

In certain embodiments, the level of systemic inflammation of thepatient is measured in order to determine a treatment strategy. Thestate of inflammation is also a marker of autonomic imbalance. Incertain embodiments, the patient may benefit from a systemic decrease ininflammation prior to, or instead of, stimulation of sympatheticstimulation to produce EPO. In certain embodiments, the level ofsystemic inflammation of the patient is monitored in order to providefeedback to a neuromodulation device.

In certain embodiments, the patient's state of inflammation is assessedusing a blood sample. The concentration of inflammatory andanti-inflammatory cytokines can be assessed. IL-6 has been shown tocauses a build-up of the glycoprotein, fibrogen in the blood, whichthickens the blood. The level of fibrogen can also be determined.

In certain embodiments, a patient's state of inflammation can bedetermined using a compound action potential (CAP) of a nerve. Such aCAP may be an intrinsic response or an evoked CAP (ECAP). There is aninverse relationship between CAP and the level of inflammation, suchthat a decrease in CAP indicates an increase in the inflammatory stateof the patient. Inflammation causes the nerve's action potential torecord slower conduction.

A compound action potential (CAP) is a signal recorded from a nervetrunk made up of numerous axons. It is the result of summation of manyaction potentials from the individual axons in the nerve trunk. U.S.Pat. No. 7,634,315, which is incorporated herein by reference in itsentirety, describes systems and methods for acquiring a nerve's CAP thatmay be used to assess a patient's inflammatory state according tocertain embodiments.

FIGS. 6A-6B illustrates a method for determining a patient's state ofinflammation that can be used during the diagnostic stage to determineappropriate therapy and/or as feedback for a closed loop system duringtreatment. In the illustrated embodiment, a compound action potential(CAP) of a nerve trunk is used to detect a patient's level ofinflammation. In an embodiment illustrated in FIG. 6A, a patient'sbaseline CAP is measured prior to the onset of an anemic state and/orwhen the patient is otherwise healthy 600 and during an anemic state610, and the measurements are compared 615. If the patient's CAP hasdecreased above a threshold, then an inflammatory state is diagnosed620. If the patient's CAP has not decreased above a threshold, then aninflammatory state is not diagnosed 630. In an embodiment illustrated inFIG. 6B, CAP values determined for patient populations are used insteadof the patient's baseline. A patient's CAP is determined during ananemic state 630. An algorithm or look-up table can be used to comparethe patient's CAP with a CAP of patients who are not in an inflammatorystate, as well as with patients having various levels of inflammation640. The patient's inflammatory state can then be determined to be thatof the inflammatory state of the patient population whose CAP is mostsimilar to that of the patient's. If the patient is determined to be inan inflammatory state, the system may first act to alleviate systemicinflammation, as described in further detail below, prior to or in lieuof sympathetic stimulation of EPO production.

Neurostimulation to Decrease Inflammation and Increase HemoglobinProduction

In an embodiment, vagal nerve stimulation is used to inhibit theproduction of pro-inflammatory cytokines that may either be initiated inresponse to the production of EPO resulting from hypoxic conditions orotherwise, and upregulate the production of NO.

Vagal nerve stimulation may be used to inhibit release ofpro-inflammatory cytokines. U.S. Pat. No. 7,869,869, filed Jan. 11,2006, entitled “Subcardiac Threshold Vagal Nerve Stimulation” and U.S.patent application Ser. No. 11/283,229, filed Nov. 18, 2005, entitled“Endovascular Lead System for Chronic Nerve Stimulation,” now abandoned,are each incorporated herein by reference in their entirety, can bemodified in accordance with certain to reduce inflammation disrupting apatient's hemoglobin production. The neural tract of the vagus nervethat modulates immune response functions at a lower firing thresholdthan cardio-inhibitory fibers. Cholinergic anti-inflammatory pathwayregulates TNF production in discrete macrophage populations via twoserially connected neurons: one preganglionic, originating in the dorsalmotor nucleus of the vagus nerve (or posterior motor nucleus of vagus),which is a cranial nerve nucleus for the vagus nerve in the medulla thatlies under the floor of the fourth ventricle; the second postganglionic,originating in the celiac-superior mesenteric plexus and projecting inthe splenic nerve. According to certain embodiments, one or both ofthese pathways are stimulated in order to reduce inflammation.

In certain embodiments, the afferent vagus nerve is also blocked inorder to avoid stimulation of other organs up-stream of theceliac-superior mesenteric plexus ganglion. In certain embodiments, therenal nerve is blocked in order to avoid an increase in blood pressureand/or an exacerbation of proinflammatory cytokine overproduction. Incertain embodiments, the renal nerve is denervated in order to avoid anincrease in blood pressure and/or an exacerbation of proinflammatorycytokine overproduction and/or avoid other consequences of anoverstimulated RAS. Renal denervation may be accomplished through, e.g.,an intravascular radiofrequency ablation catheter. U.S. Publication Nos.U.S. Publication Nos. 2013/0289650, 20130218029, 20130085489,20130282000, 20130245621, 20130090637, 20110118726, and 20110137298,each of which is incorporated herein by reference in its entirety,provides an example of a suitable apparatus that may be used todenervate the renal sympathetic nerves.

In certain embodiments, the cervical vagus is stimulated. In certainembodiments, one or both common celiac branches of the vagus nerve arestimulated.

Experimental studies in animal models suggest that SCS at lumbar spinalsegments (L2-L3) produces vasodilation in the lower limbs and feet whichis mediated by antidromic activation of sensory fibers and release ofvasoactive substances, and decreased sympathetic outflow. In certainembodiments, the spinal cord is stimulated at L2-L3 to decreasesympathetic overdrive.

Determination of EPO Stimulation Associated Inflammation

In an embodiment illustrated in FIG. 7, specificity of the EPOstimulation associated inflammation is determined using CAP. Thisinformation can be used in a closed loop system to optimize programmedparameters and to prevent EPO stimulation from exacerbating thepatient's state of inflammation.

FIG. 7 shows an exemplary method 900 that includes acquiring CAPinformation 940 and analyzing ECAP information 950. The method 900 isillustrated in conjunction with an exemplary device 901, which may be animplantable device or a device in communication with an implantabledevice, and in conjunction with ECAP information. The device 901includes a programmable microprocessor 910, control logic 930 and memory924. The control logic 930 may be in the form of instructions stored ona digital data storage medium accessible by the processor 910 where theinstructions cause the processor to perform various actions. The device901 may include any of the various features of the device 100 of FIG. 1,the programmer 1330 of FIG. 11 or the computing device 1340 of FIG. 11.

The acquisition block 940 includes acquiring a series of ECAPs, whichmay include sampling an entire ECAP, a portion of an ECAP or one or morecharacteristics of an ECAP. More specifically, ECAPs are acquired fromone or more sites along a nerve responsive to delivery of energy. Thesite of energy delivery may be the same for all of the acquired ECAPsand the ECAPs may be responsive to the same stimulus. For example, inFIG. 7, site “0” represents a site for delivery of energy while sites“X”, “Y” and “Z” represent other sites where ECAPs may be acquired.Distances between site 0 and sites X, Y and Z may be known (e.g., X mm,Y mm and Z mm) and used for analyzing acquired ECAP information. Latency(e.g., time between site 0 and another site) may be used as a relativeindication of nerve demyelination and/or other nerve condition.

An exemplary method may delivery energy at site 0 and then acquire ECAPinformation at one or more sites or an exemplary method may deliveryenergy at site 0 and then acquire ECAP information at one site, deliverenergy at site 0 and then acquire ECAP information at another site, etc.While this latter example uses one energy delivery site and multipleacquisition sites, another example may use one acquisition site andmultiple energy delivery sites. Thus, depending on delivery andacquisition technique, a method may acquire ECAP information foroverlapping segments of a nerve and/or separate segments of a nerve.

The acquisition block 940 indicates an acquisition time of T1 (time whenEPO stimulation was engaged). The analysis block 920 shows ECAPinformation for time T1 along with ECAP information for time T0 (e.g.,time when EPO stimulation is engaged), which represents a time earlierthan T1. More specifically, in the example of FIG. 7, the ECAPinformation includes latencies for conduction from site 0 to sites X, Yand Z. Further, various peaks have been identified and a latency isgiven for each peak, where possible, for example, depending onacquisition and/or analysis techniques (noting that peaks may overlapfor one site yet be distinct for another site). The ECAP information ofthe analysis block 950 may be used to assess nerve condition and mayoptionally be used to assess nerve condition with respect to nerve fibertype (e.g., where the peaks correspond to different fiber types). Hence,state of inflammation may be specific to a particular type or types ofnerve fiber. The stimulation will be conducted at an amplitude thatensures the capture of a population of neurons.

FIG. 8 shows an exemplary method 1000 for assessing EPO stimulationspecific inflammation. The method 1000 commences in a delivery block1004 that delivers energy to a nerve. The energy may be therapeuticenergy associated with stimulation of EPO production or diagnosticenergy for the purpose of diagnosing the state of inflammation. Anacquisition block 1008 acquires ECAP information responsive to thedelivered energy. The acquisition may occur at one or more sites (see,e.g., the example of FIG. 7).

An analysis block 1012 analyzes the acquired ECAP information,optionally in conjunction with previously acquired or analyzed ECAPinformation. Such an analysis may occur using an implantable deviceand/or an external device. For example, FIG. 11 shows an implantabledevice 200 in communication with an external device 1330. In thisexample, analyzing may occur solely on the implantable device 200,solely on the external device 1330 or on a combination of theimplantable device 200 and the external device 1330.

An assessment block 1016 presents information to a clinician usinganalyzed ECAP information. The information may be presented in the formof a graph, a table, an alert (buzzer, phone message, etc.) or otheruser interface. A clinician may optionally adjust one or moreoperational parameters of a therapeutic and/or a diagnostic processbased at least in part on such presented information. For example, thedevice 1330 may be capable of programming the implantable device 100using a graphic user interface that presents nerve assessmentinformation and control buttons, fields, etc. Hence, an exemplary GUImay present nerve assessment information and options for controlling animplantable device on a single GUI or a series of related and linked GUI(e.g., linked via software instructions).

An exemplary method may include implementing a nerve stimulation therapythat includes delivering stimulation energy to a target nerve (e.g., EPOstimulation and/or diagnostic), periodically acquiring compound actionpotentials responsive to the delivered stimulation energy and assessingthe patient's inflammatory state based at least in part on theperiodically acquired compound action potentials. Such a method mayacquire a compound action potential responsive to every delivery ofstimulation energy. Such a method may include renal nerve, carotid sinusnerve, periperhal nerve, and/or splenic nerve, for example, as a targetnerve.

FIG. 9 shows an exemplary method 1100 for assessing the patient'sinflammatory condition. The method 1100 commences in a delivery block1104 that delivers therapeutic energy to a nerve to stimulate EPOproduction. A subsequent block 1108 halts delivery of the therapeuticenergy to the nerve such that another delivery block 1112 can deliverydiagnostic energy to the nerve and such that an acquisition block 1116can acquire ECAP information responsive to the delivered diagnosticenergy without interference from the therapeutic energy. Once thediagnostic delivery and ECAP acquisition cycle or loop has occurred,then a block 1120 calls for the delivery of the therapeutic energy tothe nerve to resume.

An analysis block 1124 analyzes the acquired ECAP information and anassessment block 1128 may present results of the analysis to a clinicianto thereby allow a clinician to assess the patient's state ofinflammation caused by EPO stimulation. In an alternative example, animplantable device or external device may assess nerve condition and actaccordingly. For example, a device may halt delivery of therapeuticenergy to stimulate EPO production and instead begin stimulation ofnerve of the inflammatory reflex, such as the vagus nerve. While thevarious action blocks are shown in a particular order, for example, theblocks 1124 and/or 1128 may occur prior to the block 1120. Hence, inthis example, the assessment may control resumption of the therapeuticnerve stimulation.

Neurostimulation of the renal nerves could be used in conjunction withthis method in order to result in an overall reduction in inflammation,which could permit effective use of EPO produced, without acounterproductive increase in inflammation.

Anemia in Kidney Failure Patients

In the case of anemia caused by kidney failure,N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) may be used inconjunction with EPO neurostimulation and/or vagal nerve stimulation.Ac-SDKP is a naturally occurring anti-inflammatory and antifibroticpeptide. Treatment with Ac-SDKP has been shown to reduce inflammationand collagen deposition in the heart, aorta, and kidney in animal modelsof hypertension, myocardial infarction, and diabetes mellitus. Ac-SDKPhas been shown to prevent and reverse renal injury by decreasinginflammatory cell infiltration and renal fibrosis and increasing nephrinprotein.

In an embodiment, the sympathetic nervous system in kidneys is blockedto help repair kidneys, either by neuro-hyperpolarization or ablation,to stop inflammatory response but the sympathetic nerves of the carotidarteries are stimulated to indicate hypoxia in conjunction withstimulating the vagal nerve.

Nitric Oxide

Nitric oxide (NO) formed via neuronal nitric oxide synthase (nNOS) inthe brain also plays an important role in controlling renal blood flow.Areas of the brainstem with nNOS-containing neurons include the nucleustractus solitarius, ventrolateral medulla and raphe nuclei. NO fromneurons in the brain acts on the paraventricular nucleus of thehypothalamus and the rostral ventrolateral medulla and inhibits thecentral sympathetic nerve activity to the kidney, leading to renalvasodilatation and increased renal blood flow. In the brain, NOfunctions mainly as a neuromodulator.

There are also nNOS-containing neurons in sympathetic preganglionicneurons in the spinal cord. Several of the homeostatic actions of spinalafferents are brought about by the release of the transmitters NO andcalcitonin gene-related peptide (CGRP) from their peripheral endings.

Brain Stimulation

While some parasympathetic pathways may operate without directcommunication to the brain, the brain often activates efferent pathwaysand receives information via afferent pathways. Thus, the brain includesstructures associated with vagal preganglionic neurons.

Activity in the sympathetic nervous system of the spleen may be elicitedby stimulation at the hypothalamus as well. In particular, stimulationof the ventromedial nucleus of the hypothalamus is significantlycorrelated with suppression of natural killer cell cytotoxicityproduction in the spleen. Such suppression is mediated byβ-adrenoreceptors. Splenic nerve fibers terminate in close proximitywith lymphocytes expressing β-adrenoreceptors to form a synapse likestructure. The stimulation system 100, described above, can be implantedinto a person's body with stimulation lead 110 located in communicationwith a predetermined tissue and/or area of the brain. Such systems thatcan be used are described in WO2004062470, U.S. Pat. No. 7,734,340, andU.S. Pat. No. 8,239,029 each of which is incorporated herein byreference in its entirety.

The solitary tract nucleus (STN), the main terminal of vagal nerveafferents in the central nervous system, makes anatomic connections withcorticotrophin-releasing cells in the paraventricular nucleus of thehypothalamus. Imaging studies have detected activation of thehypothalamus on electrical stimulation of the vagal nerve. In anembodiment, the paraventricular nucleus of the hypothalamus isstimulated in order to decrease inflammation.

Pulse Parameters

According to various exemplary methods and/or devices described herein,a series of pulses, or a pulse train, is typically delivered by animplantable stimulation device to stimulate an autonomic nerve. Thepulse train optionally includes pulse parameters or pulse trainparameters, such as, but not limited to, frequency, pulse duration (orpulse width), number of pulses, and/or amplitude. These parameters mayhave broad ranges and vary over time within any given pulse train. Ingeneral, a power level for individual pulses and/or pulse trains isdetermined based on these parameters and/or other parameters. Exemplaryranges for pulse frequency include frequencies ranging fromapproximately 0.1 to approximately 50 Hz, and, in particular,frequencies ranging from approximately 1 Hz to approximately 7 Hz. Ithas been found in animal studies that pulse frequencies of below 1 Hzhad little to no effect on RBF. Frequencies of between about 1 and about7 Hz have been found to decrease RBF in a variety of animal models. Withfrequencies that decreased RBF, there has been shown to be an increasein renin secretion rate and antinatriuresis. Higher frequencies higherthan 50 Hz may also be suitable.

Exemplary ranges for pulse duration, or pulse width for an individualpulse (generally within a pulse train), include pulse widths rangingfrom approximately 0.01 milliseconds to approximately 5 millisecondsand, in particular, pulse widths ranging from approximately 0.1milliseconds to approximately 1.6 milliseconds. A pulse width of 0.5 mshas been shown to lower RBF in animal models of hypertension. Exemplarypulse amplitudes are typically given in terms of current or voltage;however, a pulse or a pulse trains may also be specified by power,charge and/or energy. For example, in terms of current, exemplary rangesfor pulse amplitude include amplitudes ranging from approximately 0.02mA to approximately 20 mA, in particular, ranging from 0.1 mA toapproximately 5 mA. Exemplary ranges for pulse amplitude in terms ofvoltage include voltages ranging from approximately 2 V to approximately50 V, in particular, ranging from approximately 4 V to approximately 15V. 10 V has been used in animal models to achieve a reduction in RBF.

Preconditioning

In an embodiment, the subject's kidneys are preconditioned in order tomitigate any damage to the kidneys during the induced hypoxia.Preconditioning appears to upregulate T-regulatory (Treg) lymphocytesand cell survival pathways, and downregulate apoptotic pathways. Tregcells inhibit neutrophil and macrophage accumulation in the kidney,tubular necrosis and AKI. The preconditioning may begin about two weeksprior to the EPO induction therapy. In certain embodiments, thepreconditioning may begin about one week prior to the EPO inductiontherapy.

Preconditioning may also be used to stimulate correspondent EPO receptorupregulation in the bone marrow.

Plasma EPO levels remain within observed physiologic levels inmaintenance dosing regimens, potentially reducing the risk of anyoff-target effects that could result from abnormally high orsupra-physiologic levels of EPO.

In certain embodiments, the levels of time of induced hypoxia aregraded, i.e., the cycles of hypoxia induced by neural stimulation arelonger and longer, in order to precondition the kidneys from ischemicinsult during the EPO induction therapy. In certain embodiments, thepreconditioning begins a period of time prior to the EPO inductiontherapy and the levels of time of induced hypoxia are graded during thepreconditioning.

In certain embodiment, remote ischemic preconditioning (rIPC) is used toprotect the kidneys prior to the initiation of EPO stimulation therapy.rIPC is a phenomenon whereby short periods of ischemia in one tissue canprotect a distant tissue or organ from longer periods of ischemia.Clinical trials have successfully demonstrated that rIPC used to inducetransient ischemia in limb muscles attenuated ischemia of the heart andkidneys due to hypoxic conditions during heart surgery. Since rIPC hasbeen demonstrated to attenuate systemic inflammation, rIPC may be usedto attenuate the inflammatory response during the EPO stimulationtherapy as well. rIPC may involve the release of adenosine, bradykinin,or norepinephrine and activation of K_(ATP) channels.

Oxidative stress may be attenuated by vitamins E and C administration.

Renal stimulation is optimized to achieve a target level of hemoglobin(on a longer time scale), while avoiding any detrimental change inarterial blood pressure (on a shorter time scale).

Feedback

The parameters of the EPO neurostimulation device, whether external orimplanted, may be adjusted by monitoring, e.g., serum EPO level, thehematocrit level, hemoglobin concentration, cytokine level, GFR, andrenal blood flow. The factors can be used singly or in combination toprovide feedback for adjusting EPO stimulation. In a preferred method,hemoglobin is measured, rather than hematocrit levels. Unlikehematocrit, hemoglobin is not significantly affected by shifts in plasmawater, as may occur as a consequence of diuretics or with dialysistherapy. Hemoglobin levels are directly affected by lack oferythropoietin production from the kidney and thus serve as a moreprecise measurement of erythropoiesis.

The target values of the parameters monitored may vary depending on anumber of factors, including the subject's disease state, age, physicalactivity, and gender. In an exemplary embodiment, a female Hodgkin'slymphoma patient's hemoglobin level is monitored and EPO stimulationtherapy is only rendered if the subject's hemoglobin level falls below10.5 g/dL, and then the target hemoglobin level is 10.5 g/dL or greater,but less than about 12 g/dl. In an embodiment, a male Hodgkin's lymphomapatient's hemoglobin level is monitored and EPO stimulation therapy isonly rendered if the subject's hemoglobin level falls below 12 g/dL, andthen the target hemoglobin level is 12 g/dL or greater, but less thanabout 13 g/dl.

In certain embodiments, GFR and renal blood flow are measured becausethey are prompt markers of the effectiveness of neural stimulation.

In certain embodiments, the target level of serum EPO is about 1 toabout 500 I.U./kg body weight. In certain embodiments, the target levelof serum EPO is about 50 to about 300 I.U./kg body weight. The targetlevel of serum EPO may be adjusted depending on the particular disorderbeing treated.

In certain embodiments, the hematocrit level after EPO stimulation ismonitored. The hemoglobin level is usually about one-third the value ofthe hematocrit. In certain embodiments, a target range for thehematocrit level for an adult male subjects and postmenopausal women isbetween about 30% to 37%. In certain embodiments, a target for thehematocrit level for adult male subjects and postmenopausal women isabout 36%. In certain embodiments, a target for the hematocrit level forpremenopausal women is about 33%.

In an embodiment, it is determined whether a subject is refractory toEPO stimulation, in order to determine whether neurostimulation topromote the production of anti-inflammatory cytokines and/or inhibit theproduction of inflammatory cytokines should be initiated or escalated.

In an embodiment, serum EPO levels are determined in conjunction withhemoglobin and/or hematocrit levels to determine whether eachmeasurement is within a desired range and to determine a relationshipbetween the measurements.

Whether or not a subject is refractory to EPO stimulation therapy can beassessed by determining the subject's response or predicted response totreatment with EPO stimulation. For example, in an embodiment, theresponse desired upon treatment with EPO stimulation can be defined asan increase in hemoglobin of at least 2 g/dl over a twelve (12) weekperiod. If a subject does not display such a response within therequired period of time, that subject may be deemed refractory totreatment with EPO stimulation.

A target hemoglobin level for an adult female may be 12 g/dL. A targethemoglobin level for an adult female may be 13 g/dL. Therefore, in oneembodiment, a subject is determined to be refractory to EPO stimulationtherapy if treatment over specific period of time fail to increasehemoglobin to at least 12 g/dL or 13 g/dL, respectively. Treatment ofrenal anemia to target Hb higher than 13 g/dl has been found to beharmful. Treatment of Hb below 9 g/dl has been found to providesubstantial transfusion and quality-of-life benefits, but safety isunknown. After the release of the TREAT study, the recommendations of aHb level of 10 to 12 g/dl in CKD patients seems adequate. In cancerpatients undergoing chemotherapy, some studies have shown that ahemoglobin target level of 12 g/dL or greater resulted in more rapidcancer progression or shortened overall survival in patients withbreast, head and neck, lymphoid, cervical, and non-small cell lungmalignancies. Other studies have found no statistically significantdecrease in overall survival and progression-free survival when thehemoglobin level was targeted at 12.5-13 g/dl.

In certain embodiment, the target Hb levels is 10-12 g/dl. In anembodiment, a cancer patient's hemoglobin level is monitored and EPOstimulation therapy is only rendered if the subject's hemoglobin levelfalls below 10 g/dL, and then the target hemoglobin level is 10 g/dL orless for the patient's safety. In an embodiment, anti-inflammatorycytokine therapy and or therapy inhibiting the production ofpro-inflammatories is rendered in conjunction with the EPO stimulationtherapy, and markers for inflammation are monitored, in order to reducethe likelihood that greater EPO levels will be detrimental to the cancerpatient.

The normal regulation of erythropoiesis is a feedback loop. Normalplasma EPO levels range from 10 to 30 IU/ml. In an embodiment, opticalsensors are used to complete a feedback loop. A device-based diffusereflectance sensor with two or more wavelengths of infrared and visiblelight may be used to determine total hemoglobin and/or hematocrit levelin the blood. In US Pub. No. 2010/0099964, which is incorporated hereinby reference in its entirety, O'Reilly describes a patient monitorsystem configured to measure and display a hemoglobin concentrationmeasurement suitable for use according to an embodiment of the presentinvention. According to an embodiment, after a change in EPO stimulationtherapy is made, a sensor monitors the hemoglobin level over a typicaltime course of approximately 7 days to assess the effect of the change.

Hematocrit (Hct) is the percentage of blood volume that is comprised ofred blood cells. Chronically implantable optical sensor that can measureand monitor Hct levels are known, as can be appreciated from U.S. Pat.Nos. 7,630,078, 3,847,483 and 4,114,604, each of which is incorporatedherein by reference in its entirety. Nabutovsky, in U.S. Pat. No.7,630,078, discloses implantable systems, and methods for use therewith,that compensate for changes in the intensity of light transmitted by oneor more light sources of the implantable systems. The implantable systemincludes an implantable housing including a window through which lightcan pass. Included within the housing is at least one light source, ameasurement light detector and a calibration light detector. Each lightsource transmits light of a corresponding wavelength. The intensity ofthe light transmitted by each light source is controlled by acorresponding drive signal that drives the light source. A portion ofthe light of each wavelength exits the housing through the window. Themeasurement light detector detects light of each wavelength scatteredback into the housing through the window, and produces a measurementsignal that is indicative of the intensity of the light of eachwavelength detected by the measurement light detector. The calibrationlight detector detects a portion of the light of each wavelength thathas not exited the housing, to produce a calibration signal that isindicative of the intensity of the light of the wavelength detected bythe calibration light detector, which is indicative of the intensity ofthe light transmitted by each light source. A processor detects changesin the intensity of the light transmitted by each light source based onthe calibration signal, and takes such changes in intensity into accountby making appropriate adjustments to algorithms that are used todetermine levels of hematocrit based on the measurement signal, therebyproviding a more accurate detection of the level of hematocrit.

In an embodiment, the Hct sensor is embedded into the implantablesystem. If there are existing pacing or sensing leads that are part of acardiac rhythm device, the Hct sensor can be placed on one of theexisting leads. The Hct sensor can also be placed on a standalone lead.The Hct sensor could be used either to monitor for the improvement,development, or worsening of anemia. The development of anemia may bemarked by a gradual decrease in Hct. A Hot trend could be created fromdaily or more/less frequent measurements. If a decrease greater than aprogrammable or set threshold occurs, erythropoietin therapy could beinitiated and/or the patient could be notified to contact his physician.Otherwise, he could be prompted to take an extra medication dose, forexample an iron supplement.

If there is too much erythropoietin produced, too many red blood cellsmay be produced, leading to polysythemia, which in turn can lead to anincrease in the volume of the blood in circulation, and increase in theblood's viscosity, and lead to hypertension.

Blood Pressure Sensors

An sensor may also be used for estimating blood pressure, as described,e.g., by Fayram in U.S. Pat. No. 8,147,416 and Wenzel in U.S. Pat. No.8,478,403, each of which is incorporated herein by reference in itsentirety, Fayram and Wensel disclose implantable systems, and methodsfor use therewith, for monitoring arterial blood pressure on a chronicbasis. According to the method described in Fayram, a first signalindicative of electrical activity of a patient's heart, and a secondsignal indicative of mechanical activity of the patient's heart, areobtained using implanted electrodes and an implanted sensor. Bymeasuring the times between various features of the first signalrelative to features of the second signal, values indicative of systolicpressure and diastolic pressure are determined. In specific embodiments,such features are used to determine a peak pulse arrival time (PPAT),which is used to determine the value indicative of systolic pressure.Additionally, a peak-to-peak amplitude at the maximum peak of the secondsignal, and the value indicative of systolic pressure, are used todetermine the value indicative of diastolic pressure.

According to Wenzel, for each of a plurality of periods of time, thereis a determination one or more metrics indicative of pulse arrival time(PAT), each of which are indicative of how long it takes for the leftventricle to generate a pressure pulsation that travels from thepatient's aorta to a location remote from the patient's aorta. Based onthe one or more metrics indicative of PAT, the patient's arterial bloodpressure is estimated.

Pressure Sensor

In an embodiment a CardioMEMS-type miniature pressure sensor can be usedto monitor cardiac real time performance. The CardioMEMS pressure sensoris a miniature pressure sensor having the size of a small paper pin(i.e., it can be as small as about 0.5 mm.times.2 mm.times.1.5 mm insize), which is made using the MEMS technology. It can be implantedpercutaneously via the femoral or the subclavian vein into the patient'sright atrium and transseptally into the left atrium. The CardioMEMSpressure sensor can be a wireless sensor. The fixation mechanism can bean opened hoop exerting a pressure against the pulmonary artery (PA), orthe sensor can be mounted on a stent-like component which is pressedagainst the PA inner wall with or without an anchoring mechanism such asthat of a transcatheter valve anchoring mechanism. CardioMEMS pressuresensors are developed by CardioMEMS in Atlanta, Ga.

Measuring Blood Oxygen and/or Blood Carbon Dioxide Concentration

Various sensors are known to those having ordinary skill in the art thatmay be used to measure blood oxygen and/or blood carbon dioxideconcentration. Fiber optic PCO₂ sensors and PO₂ sensors are known thatare suitable for blood concentration measurements. One example is acombined Clark-type PO₂/Stow-Severinghaus type PCO₂ sensor for sensingboth PaO₂ and PaCO₂. Other sensors include gel polymeric electrodes thatcontain a suitable electrolyte for measuring a selected parameter suchas PCO₂, PO₂, or pH. Various other sensors may be suitable includingoptical fiber pH sensors, optical fiber PCO₂ sensors, thermocoupletemperature sensors, Suitable PO₂ sensors may be electrochemical PO₂sensors or fluorescent PO₂ sensors.

Chronic Use Precautions

FIG. 12 illustrates methods invoking certain precautions in HF patientsin order to mitigate exacerbation of the underlying heart disease, andso that the neurostimulation device does not react to acute instability.

In certain embodiments, EPO stimulation is only triggered when thepatient's heart rate is within a specific heart rate range 1410. Theheart rate tolerance threshold is a programmable value specified by theclinician and may be set, e.g., in the range of 80 bpm-120 bpm. So longas the patient heart rate does not exceed the programmed tolerancethreshold, EPO stimulation may be delivered.

In certain embodiments, EPO stimulation is only triggered at night 1420.

In certain embodiments, EPO stimulation is only triggered after it isdetermined that there is not an acute instability associated with heartfailure 1430. The resolution of anemia is a chronic issue and the risksassociated with EPO stimulation may fail to outweigh the benefits duringperiods of acute instability, and other methods of treating the anemiamay be more suitable.

U.S. Publication Nos. 2013/0184545 and 2012/0190991, each of which isincorporated herein by reference in its entirety, disclose algorithmsused in accordance with certain embodiments to diagnose pulmonary fluidoverload within a patient. During a fluid overload situation, thepatient may be suffering from a dilution anemia that will be correctedusing diuretics and does not require EPO production to resolve theissue. Moreover, the fluid retention associated with congestive heartfailure may be caused by sustained reduction in renal blood flow andvasoconstriction. Thus further reduction of renal blood flow mayexacerbate the anemia.

EPO stimulation may only be performed when an algorithm determines thatthe cardiac ischemia is not ongoing 1440. In certain embodiments, animplanted device, e.g., a cardiac rhythm management device, is used todetect myocardial ischemia by evaluating electrogram features to detectan electrocardiographic change. U.S. Pat. No. 8,180,439, U.S. Pat. No.8,145,309, and U.S. Pat. No. 6,609,023, each of which is incorporatedherein by reference in its entirety, describe exemplary implantabledevices capable of detecting imminent myocardial infarctions and/ormyocardial ischemia that can be used in accordance with certainembodiments. U.S. Publication No. 201310110187, which is incorporatedherein by reference in its entirety, describes an implantable ischemiadetector configured to detect an ischemic event in the heart if anoxygen sensor signal indicates a temporary decrease in oxygenconcentration in the coronary sinus blood below a normal level followedby a temporary increase in oxygen concentration in the coronary sinusblood above the normal level.

In certain embodiments, an implantable device is used to test for heartdamage markers or cardiac enzymes in the body fluid. U.S. Pat. No.8,192,360, incorporated herein by reference in its entirety, disclosesan implantable fluid analyzer that can be used in accordance withcertain embodiments. In accordance with certain embodiments, creatinekinase (CK) can be used to diagnose or confirm the existence of heartmuscle damage. In certain embodiments, CK enzyme, CK-MB can be measuredas well. CK-MB shows an increase above normal in a person's blood testabout six hours after the start of a heart attack. It reaches its peaklevel in about 18 hours and returns to normal in 24 to 36 hours. Thepeak level and the return to normal can be delayed in a person who's hada large heart attack, especially without early and aggressive treatment.

In an embodiment, an implantable device measures the level of othercardiac muscle proteins called troponins, specifically troponin T (cTnT)and troponin I (cTnI). These proteins control the interactions betweenactin and myosin, which contracts or squeezes the heart muscle.Troponins specific to heart muscle have been found, allowing thedevelopment of blood tests (assays) that can detect minor heart muscleinjury (“microinfarction”) not detected by CK-MB. Normally the level ofcTnT and cTnI in the blood is very low. It increases substantiallywithin several hours (on average four to six hours) of muscle damage. Itpeaks at 10 to 24 hours and can be detected for up to 10 to 14 days.

An algorithm may further be used to determine that whether bleeding isongoing 1450. If bleeding is ongoing, the patient's baroreflex and bloodpressure will be abnormal. Venous return will also be abnormalirrespective of the patient's total peripheral resistance. EPOstimulation will not be initiated during this acute state.

If the algorithm determined that the specific heart rate is achieved, itis a preprogrammed time of day, such as night time, the patient is notsuffering from an acute exacerbation of heart failure, no cardiacischemia or bleeding are ongoing, then the system will trigger EPOstimulation by the neuromodulation device 1460. Anti-inflammatorystimulation, e.g., vagal nerve stimulation may also be triggeredsimultaneously with EPO production, or at a time when it is determinedthat EPO production has caused inflammation 1470.

Drug Pump

In further embodiments, it may be desirable to use a drug deliverysystem independently or in combination with electrical stimulation toresult in the stimulation parameters of the present invention or toenhance the effectiveness of the stimulation therapy. Drug delivery maybe used independent of or in combination with a lead/electrode toprovide electrical stimulation and chemical stimulation. When used, thedrug delivery catheter is implanted such that the proximal end of thecatheter is coupled to a pump and a discharge portion for infusing adosage of a pharmaceutical or drug. Implantation of the catheter can beachieved by combining data from a number of sources including CT, MRI orconventional and/or magnetic resonance angiography into the stereotactictargeting model. Thus, implantation of the catheter can be achievedusing similar techniques as discussed above for implantation ofelectrical leads, which is incorporated herein. The distal portion ofthe catheter can have multiple orifices to maximize delivery of thepharmaceutical while minimizing mechanical occlusion. The proximalportion of the catheter can be connected directly to a pump or via ametal, plastic, or other hollow connector, to an extending catheter.

Still further, the present invention can comprise a chemical stimulationsystem that comprises a system to control release of neurotransmitters(e.g., norepinephrine, epinephrine), chemicals (e.g., zinc, magnesium,lithium) and/or pharmaceuticals that are known to alter the activity ofneuronal tissue. For example, infusion formulation delivery system canutilize a control system having an input-response relationship. A sensorgenerates a sensor signal representative of a system parameter input(such as levels of neurotransmitters), and provides the sensor signal toa controller. The controller receives the sensor signal and generatescommands that are communicated to the infusion formulation deliverydevice. The infusion formulation delivery device then delivers theinfusion formulation output to the predetermined site at a determined.

It should be appreciated from the above that the various structures andfunctions described herein may be incorporated into a variety ofapparatuses (e.g., a stimulation device, a lead, a monitoring device,etc.) and implemented in a variety of ways. Different embodiments ofsuch an apparatus may include a variety of hardware and softwareprocessing components. In certain embodiments, hardware components suchas processors, controllers, state machines, logic, or some combinationof these components, may be used to implement the described componentsor circuits.

In certain embodiments, code including instructions (e.g., software,firmware, middleware, etc.) may be executed on one or more processingdevices to implement one or more of the described functions orcomponents. The code and associated components (e.g., data structuresand other components used by the code or used to execute the code) maybe stored in an appropriate data memory that is readable by a processingdevice (e.g., commonly referred to as a computer-readable medium).

Moreover, some of the operations described herein may be performed by adevice that is located externally with respect to the body of thepatient. For example, an implanted device may send raw data or processeddata to an external device that then performs the necessary processing.

The components and functions described herein may be connected orcoupled in many different ways. The manner in which this is done maydepend, in part, on whether and how the components are separated fromthe other components. In certain embodiments some of the connections orcouplings represented by the lead lines in the drawings may be in anintegrated circuit, on a circuit board or implemented as discrete wiresor in other ways.

The signals discussed herein may take various forms. For example, incertain embodiments a signal may comprise electrical signals transmittedover a wire, light pulses transmitted through an optical medium such asan optical fiber or air, or RF waves transmitted through a medium suchas air, and so on. In addition, a plurality of signals may becollectively referred to as a signal herein. The signals discussed abovealso may take the form of data. For example, in certain embodiments anapplication program may send a signal to another application program.Such a signal may be stored in a data memory.

Moreover, the recited order of the blocks in the processes disclosedherein is simply an example of a suitable approach. Thus, operationsassociated with such blocks may be rearranged while remaining within thescope of the present disclosure. Similarly, the accompanying methodclaims present operations in a sample order, and are not necessarilylimited to the specific order presented.

Also, it should be understood that any reference to elements hereinusing a designation such as “first,” “second,” and so forth does notgenerally limit the quantity or order of those elements. Rather, thesedesignations may be used herein as a convenient method of distinguishingbetween two or more different elements or instances of an element. Thus,a reference to first and second elements does not mean that only twoelements may be employed there or that the first element must precedethe second element in some manner. Also, unless stated otherwise a setof elements may comprise one or more elements.

Closed-Loop System

Referring to FIG. 13, a closed-loop system is used to more safely andefficiently stimulate EPO. In block 1305, the stimulation device 100monitors the hemoglobin levels of the patient on a continual (e.g.,periodic) basis. If anemia is not indicated, the operational flow mayproceed back to block 1310 whereby the stimulation device 100 continuesto monitor the hemoglobin levels of the patient. In the event anemia isindicated, the operational flow proceeds to block 1315.

At block 1315, the anemia monitor 240 (or some other suitable functionalcomponent of the device 100 such as a neuromodulation stimulationcontroller 239) may select parameters for electrical stimulation basedon one or more characteristics of the indicated anemic condition. Insome aspects, depending on whether the characterization of the anemiccondition indicates anemia, a decision may be made by the anemia monitor240 to provide stimulation of parasympathetic innervation, sympatheticinnervation, or a combination of the two 1320. Here, in an embodimentwhere the stimulation device 100 is coupled to different stimulationleads (e.g., neurological lead 110) a decision may be made regardingwhich leads are to be used for the stimulation operation. For example,if autonomic imbalance or an inflammatory state is indicated, theparasympathetic system may be activated (e.g., to balance out anautonomic sympathetic response) and/or the sympathetic systemdeactivated. In this case, the heart rate of the patient may decrease asa result of the stimulation of one or more parasympathetic nerves.Conversely, if anemia due to sympathetic withdrawal is indicated, thesympathetic system may be activated (e.g., to balance out an autonomicparasympathetic response) and/or the parasympathetic system may bedeactivated. In this case, the heart rate of the patient may increase asa result of the stimulation of one or more sympathetic nerves.

In addition, signal parameters such as signal frequency and/or signalamplitude may be selected based on the indicated anemic condition. Forexample, different parameters may be used for parasympatheticinnervation versus sympathetic innervation.

In some implementations the anemia monitor 240 may select one or more ofthese parameters based on the severity of the anemic condition. Forexample, if the anemic condition is not severe, a relatively smallsignal magnitude and/or a relatively low frequency may be selected forthe stimulation operation. Conversely, if the anemic condition isrelatively severe, a relatively large signal magnitude and/or arelatively high frequency may be selected for the stimulation operation.

Also, in some aspects the length of time that a stimulation signal is tobe applied may be based on the anemic condition. For example, the anemiamonitor 310 may designate stimulation duration times based on whetheranemia is indicated and/or based on the severity of the anemiccondition.

As represented by block 1330, the stimulation device 100 may thengenerate one or more stimulation signals to stimulate the patient'snervous system. To this end, the stimulation device 100 may include aneurostimulation signal generator 312 (e.g., comprising a pulsegenerator) that is coupled to at least one nerve stimulation lead (e.g.,neurological lead 104). Here, the at least one nerve stimulation leadmay be implanted to stimulate one or more parasympathetic nerves and/orimplanted to stimulate one or more sympathetic nerves. In someimplementations, the neurosignal generator 238 may be configured togenerate a bi-polar square wave or some other waveform suitable fornerve stimulation.

As represented by block 1335, during and/or after stimulation of thenervous system, the stimulation device 100 may monitor cardiac activity(e.g., by processing acquired IEGM data) to determine the effect of thestimulation on the patient's condition and adapt the stimulationaccordingly. In certain embodiments, impedance sensors are used todetermine the stroke volume, cardiac output to monitor the cardiacstatus to ensure no sludge formation and ensure systemic integrity.Impedance sensors for alignment of RBCs (cells are aligned: impedance islow)—check integrity of blood quality at the level of the heart(endocardial blood volume). In particular, the impedance of highfrequency current driven in parallel to the aorta, for example from thechest to the abdomen, should have larger decreases during systole versusthat measured during diastole, indicating a higher hematocrit overall(high impedance during diastole because of many RBCs randomlydistributed, disturbing the electric field in the great vessels) andbetter overall flow (low impedance during systole because of the highdegree of parallel alignment of RBCs in the ascending and descendingaorta allowing current to flow freely).

U.S. Publication No. 2012/0239104 (“Rosenberg”), incorporated herein byreference in its entirety, describes a method that can be used accordingto an embodiment to measure cardiogenic impedance from one or morevectors, preferably multiple vectors, to measure cardiac integrity thatcan be used to determine whether EPO therapy should be triggered and/orfor feedback in a closed loop system. Rosenberg provides a method formeasuring cardiogenic impedance (CI) along at least a first vector todetermine stroke volume, venous return, cardiac contractility status,and ejection times.

Changes in contractility also produce significant changes in ejectionfraction (EF). Increasing contractility leads to an increase in EF,while decreasing contractility decreases EF. Therefore, EF is often usedas a clinical index for evaluating the inotropic state of the heart. Inheart failure, for example, an associated decrease in contractilityleads to a fall in stroke volume as well as an increase in preload,thereby decreasing EF. The increased preload, if it results in a leftventricular end-diastolic pressure greater than approximately 20 mmHg,can lead to pulmonary congestion and edema. Treatment of a patient inheart failure with an inotropic drug (e.g., beta-adrenoceptor agonist ordigoxin) shifts the depressed Frank-Starling curve up and to the left,thereby increasing stroke volume, decreasing preload, and increasing EF.

For example, as represented by block 1318, the stimulation may bemodified if the severity of the anemic condition has changed, if thepatient's heart rate has changed, if there has been a change in thequantity or severity of observed PVCs, if there has been a change incardiac integrity, and so on. In the even that EPO stimulation causes animbalance of the autonomic nervous system, as indicated by a detrimentto cardiac integrity, the parameters of stimulation of the nerves may bealtered, as disclosed in, e.g., U.S. Pat. No. 6,937,896, discussedabove, to improve cardiac integrity.

As a specific example, if the stimulation has mitigated the severity ofthe response to the anemic condition, the amplitude and/or the frequencyof the stimulation signal may be decreased. Similarly, if anemia is nolonger indicated, the application of stimulation may be terminated, asrepresented by block 1320. In any event, the stimulation device 100 maycontinue to monitor the patient's condition over time and apply anappropriate level of neurostimulation whenever it is warranted.

As mentioned above, in some implementations the teaching herein may beimplemented in an implantable cardiac device that is used to monitorand/or or treat cardiac various conditions. The following descriptionsets forth an exemplary implantable cardiac device (e.g., a stimulationdevice such as an implantable cardioverter defibrillator, a pacemaker,etc.) that is capable of being used in connection with the variousembodiments that are described herein. It is to be appreciated andunderstood that other devices, including those that are not necessarilyimplantable, can be used and that the description below is given, in itsspecific context, to assist the reader in understanding, with moreclarity, the embodiments described herein.

Transcutaneous Neuromodulation for Treatment of Anemia

Transcutaneous Electrical Nerve Stimulation (TENS) and transcutaneousspinal electroanalgesia (TSE) devices have been used to manage pain incancer patients (palliative treatment). An external stimulation deviceis similarly used on an acute basis to treat anemia in, for example,cancer patients, according to certain embodiments of the claimedinvention. FIG. 14 illustrates an external neuromodulation system 1410.

As illustrated, a transcutaneous electrical nerve stimulation device1410 is used to stimulate nerves of the neck 1420 involved in renalblood flow regulation and/or the inflammatory reflex. According tocertain embodiments, a transcutaneous electrical nerve stimulationdevice is used to stimulate the right and/or carotid sinus nerve alsoknown as the Hering's nerve), which is a branch of the ninth cranialnerves (CN IX), also known as the glossopharyngeal nerve (GPN). Theright and left CSN include afferent fibers that convey information tothe brain. The central nervous system may then trigger stimulation ofthe efferent nerves of the kidneys, and effect renal blood flow.Stimulation in the cervical region may also affect chemosensingactivities of a carotid body, which can increase catecholamineproduction through communication with the central nervous system.

U.S. Publication No. 2013/0131753 (“Simon”), U.S. Pat. Nos. 4,702,254,4,867,164 5,025,807, and 5,540,734, the disclosures of which areincorporated herein by reference in their entirety, provide appropriatetechniques and devices amenable to transdermally stimulates of autonomicnerves in the area of the neck using electrical and/or magneticstimulation, in accordance with certain embodiments of the claimedinvention. As disclosed in Simon, a time-varying magnetic field,originating and confined to the outside of a patient, generates anelectromagnetic field and/or induces eddy currents within the tissue ofthe patient. Magnetic stimulation is non-invasive because the magneticfield is produced by passing a time-varying current through a coilpositioned outside the body. An electric field is induced at a distancecausing electric current to flow within electrically conducting bodilytissue. U.S. Patent Publication Nos. US2005/0075701 and US2005/0075702,the disclosures of which are incorporated herein by reference in theirentirety, describe pulse generators that may be used in an embodiment.

U.S. Publication No. US2005/0216062 (“Herbst”), the disclosures of whichare incorporated herein by reference in their entirety, discloses asystem for stimulating, blocking and/or modulating impulse to theelectrodes or coils used non-invasively to stimulate deep nerves, usedin certain embodiments. Herbst discloses a multifunctional electricalstimulation (ES) system adapted to yield output signals for effectingelectromagnetic or other forms of electrical stimulation for a broadspectrum of different biological and biomedical applications, whichproduce an electric field pulse in order to non-invasively stimulatenerves. The system includes an ES signal stage having a selector coupledto a plurality of different signal generators, each producing a signalhaving a distinct shape, such as a sine wave, a square or a saw-toothwave, or simple or complex pulse, the parameters of which are adjustablein regard to amplitude, duration, repetition rate and other variables.

Alternatively, or in addition, nerves of the spinal cord 1430 involvedin renal blood flow regulation may be stimulated transcutaneously.Specifically, nerves in the T10-L1 region 1440 of the patient's spinemay be stimulated. Generally, sympathetic innervation of the kidneyscomes from the 10th through 12th thoracic spinal nerves, but can arisefrom as high as T6 and as low as L2, especially on the patient's rightside. In certain embodiments, nerves in the T2-L2 region are stimulated.

U.S. Publication Nos, 2010/0152817 and 2012/0022612, the disclosure ofeach is incorporated herein by reference in its entirety, provideappropriate techniques and devices amenable to transdermally stimulatesof autonomic nerves in the area of the spinal cord that can be used inaccordance with certain embodiments to treat anemia in accordance withcertain embodiments of the claimed invention.

A pre-pulse may be used in order to prepare the Na⁺ channels of neuronsin the spinal cord for activation in order to recruit more neurons.

As illustrated in FIG. 14, the external system may also include asurface EKG monitor 1450 and an external blood pressure monitor 1460,such as a blood pressure cuff, for use in a closed-loop system fordetermining the effect of the therapy, as described in further detailherein. Heart rate and heart rate variability may be monitored via theEKG and contractility can be monitored via arterial pressure sensors(e.g., the time derivative of the pressure can provide a good measure ofcontractility).

Renal Denervation

Methods of renal denervation are well known in the art. Safety andefficacy of a novel multi-electrode renal denervation catheter inresistant hypertension: 3 month data from the EnligHTN I trial, WorthleyS., Tsioufis C., Worthley M., Sinhal A., Chew D., Meredith I., MalaiapanY., Papademetriou V., Journal of the American College of Cardiology 201260 SUPPL, 17 (B62), incorporated herein by reference in its entirety,describes a method of renal denervation using the EnligHTN™ catheter,describes a method wherein a renal artery CT angiography is performed atbaseline and repeated at 6 months. Utilizing femoral artery access withan 8Fr RDC guiding sheath the EnligHTN catheter is introduced into therenal artery, and RF energy delivered sequentially for 90 seconds perelectrode. The catheter is repositioned, rotated and denervationrepeated. Both renal arteries may be treated. Laparoscopic renaldenervation may be used as an alternative or in conjunction withcatheter radiofrequency ablation in order to safely affect a morecomplete renal denervation. An example of such an approach is describedin Valente, in Laparoscopic Renal Denervation for IntractableADPK-Related Pain, Nephrol Dial Transplant 16:60 (2001), incorporatedherein by reference in its entirety.

Methods of radiofrequency catheter ablation are described in U.S.Publication Nos. 2013/0218029, 2013/0085489, 2013/0245621, 2013/0090637,2011/0118726, and 2011/0137298, each of which is incorporated herein byreference in its entirety. Complete renal denervation is not required tosignificantly lower blood pressure and central nervous system overactivity. Typical use of radiofrequency ablation catheters does notresult in complete renal denervation. As illustrated in the methoddescribed in FIG. 15, a radiofrequency catheter ablation device is usedto ablate the renal nerves of a patient 1510. The lead may be taken outof the patient and replaced with a permanently implantable lead, or theRF ablation catheter can be modified to provide a lead that ispermanently implantable into the patient after a renal denervationprocedure 1520 and configured for neurostimulation. In an embodiment,electrodes 22 illustrated in FIG. 3A above used for RF ablation may alsobe used for neuromodulation (either stimulation or block) as well. In anembodiment, separate electrodes 22 may be used for ablation andneuromodulation in order to minimize damage caused to the renal vesselby maneuvering the device. The tip of the lead may be secured distal tothe ablation site 1530 in order to neuromodulate the remaining unablatednerves to produce EPO in accordance with the disclosure herein. Such anembodiment may be especially appropriate in the event thatradiofrequency catheter ablation is performed in conjunction withlaparoscopic renal denervation, where the more of the renal nerves maybe denervated.

In the event that renal denervation results in anemia, neuromodulationof the central nervous system can alternatively, or additionally, beused to reverse the anemia, as described herein. According to the methodillustrated in FIG. 15, the carotid sinus nerves, afferent renal nervesof the spinal cord (by stimulating the spinal cord at T10-L1), and/orthe brain in order to stimulate the remaining efferent renal nervesthrough central nervous system stimulation and/or to stimulate theproduction of catecholamines and neuropeptides 1540.

It should be appreciated that various modifications may be incorporatedinto the disclosed embodiments based on the teachings herein. Forexample, the structure and functionality taught herein may beincorporated into types of devices other than the specific types ofdevices described above. Also, different types of stimulation signalsmay be applied to the nervous system consistent with the teachingsherein. In addition, neurostimulation signals may be applied to otherlocations consistent with the teachings herein. Furthermore, adetermination to apply neurostimulation may be made based on anemicconditions that are indicated in other ways consistent with theteachings herein.

Although example steps are illustrated and described, the presentinvention contemplates two or more steps taking place substantiallysimultaneously or in a different order. In addition, the presentinvention contemplates using methods with additional steps, fewer steps,or different steps, so long as the steps remain appropriate forimplanting stimulation system 10 into a person for electricalstimulation of the predetermined site.

It should be appreciated from the above that the various structures andfunctions described herein may be incorporated into a variety ofapparatuses (e.g., a stimulation device, a lead, a monitoring device,etc.) and implemented in a variety of ways. Different embodiments ofsuch an apparatus may include a variety of hardware and softwareprocessing components. In certain embodiments, hardware components suchas processors, controllers, state machines, logic, or some combinationof these components, may be used to implement the described componentsor circuits.

In certain embodiments, code including instructions (e.g., software,firmware, middleware, etc.) may be executed on one or more processingdevices to implement one or more of the described functions orcomponents. The code and associated components (e.g., data structuresand other components used by the code or used to execute the code) maybe stored in an appropriate data memory that is readable by a processingdevice (e.g., commonly referred to as a computer-readable medium).

Moreover, some of the operations described herein may be performed by adevice that is located externally with respect to the body of thepatient. For example, an implanted device may send raw data or processeddata to an external device that then performs the necessary processing.

The components and functions described herein may be connected orcoupled in many different ways. The manner in which this is done maydepend, in part, on whether and how the components are separated fromthe other components. In certain embodiments some of the connections orcouplings represented by the lead lines in the drawings may be in anintegrated circuit, on a circuit board or implemented as discrete wiresor in other ways.

The signals discussed herein may take various forms. For example, incertain embodiments a signal may comprise electrical signals transmittedover a wire, light pulses transmitted through an optical medium such asan optical fiber or air, or RF waves transmitted through a medium suchas air, and so on. In addition, a plurality of signals may becollectively referred to as a signal herein. The signals discussed abovealso may take the form of data. For example, in certain embodiments anapplication program may send a signal to another application program.Such a signal may be stored in a data memory.

Moreover, the recited order of the blocks in the processes disclosedherein is simply an example of a suitable approach. Thus, operationsassociated with such blocks may be rearranged while remaining within thescope of the present disclosure. Similarly, the accompanying methodclaims present operations in a sample order, and are not necessarilylimited to the specific order presented.

Also, it should be understood that any reference to elements hereinusing a designation such as “first,” “second,” and so forth does notgenerally limit the quantity or order of those elements. Rather, thesedesignations may be used herein as a convenient method of distinguishingbetween two or more different elements or instances of an element. Thus,a reference to first and second elements does not mean that only twoelements may be employed there or that the first element must precedethe second element in some manner. Also, unless stated otherwise a setof elements may comprise one or more elements.

While certain embodiments have been described above in detail and shownin the accompanying drawings, it is to be understood that suchembodiments are merely illustrative of and not restrictive of theteachings herein. In particular, it should be recognized that theteachings herein apply to a wide variety of apparatuses and methods. Itwill thus be recognized that various modifications may be made to theillustrated embodiments or other embodiments, without departing from thebroad scope thereof. In view of the above it will be understood that theteachings herein are intended to cover any changes, adaptations ormodifications which are within the scope of the disclosure as defined byany claims associated herewith.

1. A method of treating anemia in a human patient, the methodcomprising: monitoring the hemoglobin levels of the patient on aperiodic basis; determining an anemic condition based on the hemoglobinlevel; selecting electrical stimulation parameters of a neurostimulationdevice based on one or more characteristics of the indicated anemiccondition; and generating one or more stimulation signals to stimulatethe patient's nervous system; and monitoring at least one of anautonomic balance and inflammatory state of the patient resulting fromthe neurostimulation.
 2. The method of claim 1 further comprisingdetermining whether to provide stimulation of parasympatheticinnervation, sympathetic innervation, or a combination of the two basedon the anemic condition of the patient.
 3. The method of claim 1 furthercomprising: monitoring the patient's cardiac activity; and adapting thestimulation parameters based on the patient's cardiac activity.
 4. Themethod of claim 1, further comprising: monitoring changes in at leastone of: a severity of the anemic condition, a patient's heart rate, aquantity or severity of observed PVCs, and cardiac integrity; andmodifying stimulation parameters if there is a change in at least oneof: the severity of the anemic condition, the patient's heart rate, thequantity or severity of observed PVCs, and the cardiac integrity.
 5. Themethod of claim 1, wherein determining an anemic condition based on thehemoglobin level comprises determining the patient's EPOobserved/predicted (O/P) ratio.
 6. The method of claim 1, whereindetermining an anemic condition based on the hemoglobin level comprisesdetermining the patient's EPO observed/predicted O/P ratio, transferrinsaturation, and ferritin level.
 7. A system for treating anemia in ahuman patient comprising: an external neural stimulator configured tostimulate at least one of a sympathetic and parasympathetic nerve in thepatient's neck or spine, wherein stimulation of the sympathetic nerveeffects renal blood flow and stimulation of the parasympathetic nervedecreases the patient's inflammation state; an external cardiac sensorconfigured to monitor the patient cardiac activity, configured toprovide the external neural stimulator with feedback for determiningstimulation parameters.
 8. The system of claim 7 further comprising apulse generator configured to generate a pre-pulse prior to generating atherapeutic pulse to the neck or spinal cord in order to prepare the Na⁺channels of neurons in the spinal cord and neck for activation.
 9. Amethod comprising: implementing a nerve stimulation therapy within abody that comprises delivering a therapeutic stimulation energy to atarget nerve in order to stimulate EPO production; temporarily haltingthe delivering therapeutic stimulation energy to the target nerve;during the halting, delivering diagnostic stimulation energy to thetarget nerve; acquiring a compound action potential responsive to thedelivered non-therapeutic stimulation energy; recommencing thedelivering therapeutic stimulation energy to the target nerve; andassessing a level of inflammation caused by the delivering therapeuticstimulation energy to the target nerve based at least in part on theacquired compound action potential.
 10. The method of claim 9, furthercomprising initiating vagal nerve stimulation when the patient's levelof inflammation has increased above a threshold level.
 11. A method oftreating anemia in a human patient comprising: ablating renal nerves ofa patient using an ablation catheter; permanently implanting one or moreneuromodulation leads into the patient; applying neurostimulation to atleast one of a parasympathetic and sympathetic nerve using theneuromodulation lead to therapeutically treat the patient's anemia. 12.The method of claim 11 wherein the lead is implanted into the renalvasculature of the patient, and wherein the neurostimulation is appliedto the nerves of the renal vasculature.
 13. The method of claim 11wherein the ablation catheter is configured for both permanent ablationand non-permanent electrically modulate nerves.
 14. The method of claim11 further comprising using the one or more neuromodulation leads toneuromodulate the central nervous system in order to stimulate theproduction of catecholamines and neuropeptides.
 15. The method of claim11 further comprising using one or more neuromodulation leads toneuromodulate the vagal nerve of the patient in order to reduceinflammation and/or restore autonomic balance.
 16. A method oftriggering neurostimulation to treat anemia in a heart failure patient,the method comprising: using a microprocessor within a neurostimulationdevice to determine triggering conditions, wherein the triggeringconditions comprise: the patient's heart rate is within a specific heartrange; the patient's heart condition is stable; and cardiac ischemia isnot ongoing; and initiating neurostimulation using the neuromodulationdevice to treat anemia when the triggering conditions are determined tobe met.
 17. The method of claim 16, wherein neurostimulation comprisesstimulation of a sympathetic nerve effecting EPO production.
 18. Themethod of claim 16, wherein neuromodulation comprises stimulation of aparasympathetic nerve affecting inflammation.
 19. The method of claim16, wherein the parasympathetic nerve is the vagus nerve.
 20. The methodof claim 16, wherein the vagus nerve is a vagus nerve innervating theceliac-superior mesenteric plexus ganglion.
 21. The method of claim 16,wherein the vagus nerve is a cervical vagus nerve.
 22. The method ofclaim 16, wherein the triggering conditions further comprise: bleedingis not ongoing.
 23. The method of claim 16, wherein the triggeringconditions further comprise: a preprogrammed time of day.
 24. The methodof claim 16, further comprising obtaining cardiogenic impedancemeasurements from a plurality of vectors using a stimulation device todetermining cardiac integrity and using cardiac integrity for feedbackin determining stimulation parameters of the EPO stimulation.
 25. Amethod of treating anemia in a human patient, the method comprising:surgically implanting an electrode in communication with at least onepredetermined site selected from the group consisting of one or morebrain regions, a renal vessel, a carotid sinus nerve, one or more areasof the spinal cord, one or more vagus nerves; therapeutically treatinganemia by generating an electrical signal with the pulse generatingsource, wherein said signal electrically stimulates the at least onepredetermined site; determining an amount of inflammation caused by theelectrical signal; and automatically adjusting the control parametersand/or the predetermined site of stimulation of the pulse generatingsource based on at least the determined amount of inflammation.
 26. Themethod of claim 25, wherein the at least one predetermined sitecomprises the NF-κB pathway of the hypothalamus, and wherein theelectrical signal blocks the NF-κB pathway of the hypothalamus.
 27. Themethod of claim 25, wherein the at least one predetermined sitecomprises an area of the spinal cord at T10-L2, the renal artery, theparaventricular nucleus of the hypothalamus, the cervical vagus nerve,and the NF-κB pathway of the hypothalamus.